tag:blogger.com,1999:blog-57601457676607877852024-03-13T10:53:14.337-07:00Autism-Associated Gene SpotlightLindsayhttp://www.blogger.com/profile/10860246538349067232noreply@blogger.comBlogger3125tag:blogger.com,1999:blog-5760145767660787785.post-32166898631527056622016-01-14T15:59:00.002-08:002016-01-14T16:00:54.345-08:00Gene Spotlight: SLC4A10<span style="font-family: trebuchet ms;">(Cross-posted from <a href="http://autistscorner.blogspot.com/2010/11/autism-related-gene-spotlight-slc4a10.html">my other blog</a>)</span><br />
<span style="font-family: trebuchet ms;"><em><strong><br /></strong></em></span>
<span style="font-family: trebuchet ms;"><em><strong>EXECUTIVE SUMMARY:</strong> SLC4A10 is a member of a large family of genes that encode proteins for transporting ions (charged particles) across cell membranes. Within that (super)family, SLC4A10 belongs to a family of transporter proteins specializing in bicarbonate (HCO<sub>3</sub><sup>-</sup>) ion transport, which is important for maintaining a constant pH within the cell --- i.e., preventing it from becoming too acidic or basic for the cell's biological machinery to function. SLC4A10 encodes a version of this transporter protein specific to certain cells of the central nervous system, and mutations disrupting this gene have been found in two instances: first, in a set of autistic twins who participated in a genomic study, and second, in a girl with epilepsy and intellectual disability. Disruption of this gene is thought to make brain cells more excitable, which can lead to seizures (which is probably why the girl in the second case study has them).</em></span>
<span style="font-family: Trebuchet MS;">____________________________________________________________</span><br />
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<span style="font-family: trebuchet ms;"><strong>Where is it?</strong></span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Its <a href="http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation">"cytogenetic band"</a> is given as 2q23-q24 (or, alternatively, 2q24.2), which means that it's on the long arm ("q" as opposed to "p") of chromosome 2, somewhere in the middle. </span>
<span style="font-family: Trebuchet MS;">Here's a map of chromosome 2, with a red line marking where <em>SLC4A10</em> is:</span>
<img alt="" border="0" id="BLOGGER_PHOTO_ID_5537291015590136034" src="http://4.bp.blogspot.com/_CGQTWjODmZw/TNho10I2SOI/AAAAAAAAAjk/uP_ATwVAGJQ/s400/chromosome+2+map.bmp" style="cursor: hand; display: block; height: 50px; margin: 0px auto 10px; text-align: center; width: 400px;" /><span style="font-family: trebuchet ms;">This gene spans 360,942 base pairs (which is fairly large, but not enormous; there's a lot of variability in gene size, with the smallest ones only a few hundred bases long and the largest spanning several million bases --- see <a href="http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=hmg&part=A642">this e-textbook chapter</a> for details), covering the distance between bases 162,480,845 and 162,841,786 (measuring from the <a href="http://en.wikipedia.org/wiki/Centromere">centromere</a> to the end of the chromosome). </span><br />
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<span style="font-family: trebuchet ms;"><strong>What does it do?</strong></span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">The name <em>SLC4A10</em> refers to its membership in a family of genes encoding similar proteins: <a href="http://en.wikipedia.org/wiki/Solute_carrier_family">solute carrier family</a> (SLC) 4, which is a group of ten genes whose protein products transport <a href="http://en.wikipedia.org/wiki/Bicarbonate">bicarbonate</a> ions (HCO<sub>3</sub><sup>-</sup>) across cell membranes.</span>
<a href="http://4.bp.blogspot.com/_CGQTWjODmZw/TNiAHpin2nI/AAAAAAAAAj0/_jZyk5XrWzE/s1600/bicarbonate+ion.png"><img alt="" border="0" id="BLOGGER_PHOTO_ID_5537316610750536306" src="http://4.bp.blogspot.com/_CGQTWjODmZw/TNiAHpin2nI/AAAAAAAAAj0/_jZyk5XrWzE/s200/bicarbonate+ion.png" style="cursor: hand; float: left; height: 135px; margin: 0px 10px 10px 0px; width: 200px;" /></a>
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<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Bicarbonate ion (and its protonated form, <a href="http://en.wikipedia.org/wiki/Carbonic_acid">carbonic acid</a>, which is readily synthesized from <a href="http://en.wikipedia.org/wiki/Carbon_dioxide">carbon dioxide</a> and hydrogen ions) plays a central role in regulating <a href="http://en.wikipedia.org/wiki/PH">pH</a>, both within cells and outside of them, as in blood. pH is a measure of acidity, expressed as the (negative) logarithm of the concentration of hydrogen ions (H<sup>+</sup>) in the fluid being tested. Pure water has a "neutral" pH of 7 (meaning that, of the H<sub>2</sub>O molecules making up liquid water, an approximately equal number exist in their dissociated forms of H<sup>+</sup> and <sup>-</sup>OH at any given time --- if an acidic or basic compound is added, it will either add or remove H+ to the solution, and thus move the pH down or up); the water inside human bodies is slightly basic and has a pH of around 7.4 ("physiological pH"). </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Bicarbonate/carbon dioxide can act as a "buffer" between an acidic or basic substance and the physiological environment: depending on what form it's in, it can either donate (H<sub>2</sub>CO<sub>3</sub> --> HCO<sub>3</sub><sup>-</sup> --> CO<sub>3</sub><sup>2-</sup>) or receive (CO<sub>3</sub><sup>2-</sup> --> HCO<sub>3</sub><sup>-</sup> --> H<sub>2</sub>CO<sub>3</sub>) hydrogen ions and keep the surrounding fluid from having to disrupt <em>its</em> acid-base equilibrium.</span><br />
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<span style="font-family: Trebuchet MS;">Because bicarbonate cannot diffuse across cell membranes by itself, it needs to be transported into cells by <a href="http://rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/carriers.htm">ion-exchanging membrane proteins</a> whenever it is needed. The protein produced by <em>SLC4A10</em> ferries bicarbonate ion and sodium ion into the cell while expelling a chloride ion from the cell. Two bicarbonate ions are imported for every sodium ion, which keeps the net gain/loss of electrical charge at zero. </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">This particular gene is primarily expressed in the central nervous system (i.e., the brain and spinal cord), though related genes encode similar bicarbonate-transporting proteins for other tissue types. In mice, <em>SLC4A10</em> is expressed in some types of brain tissue but not in others: it was specific to <a href="http://en.wikipedia.org/wiki/Gray_matter">gray matter</a> (<a href="http://en.wikipedia.org/wiki/Neuron">neurons</a>, but not <a href="http://en.wikipedia.org/wiki/Glial_cell">glial cells</a>), and was not expressed in <a href="http://en.wikipedia.org/wiki/White_matter">white matter</a>; and it was also specific to certain regions of the brain: the <a href="http://en.wikipedia.org/wiki/Olfactory_bulb">olfactory bulb</a>, <a href="http://en.wikipedia.org/wiki/Cerebral_cortex">cortex</a>, hippocampus and <a href="http://en.wikipedia.org/wiki/Cerebellum">cerebellum</a>. </span><br />
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<span style="font-family: Trebuchet MS;">In <a href="http://en.wikipedia.org/wiki/Neuron">neurons</a>, ion concentrations inside and outside the cell play a role in whether a given neuron will "fire" --- undergo <a href="http://faculty.washington.edu/chudler/ap.html">dramatic and rapid change in the electrical potential difference across its membrane</a>, which triggers electrical and/or chemical signaling of adjacent neurons --- so ion transporters in neurons also help mediate <a href="http://en.wikipedia.org/wiki/Neurotransmission">neurotransmission</a>.</span><br />
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<span style="font-family: Trebuchet MS;"><strong>What mutant versions of this gene have been discovered?</strong></span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">In the article I mentioned in <a href="http://autistscorner.blogspot.com/2010/11/autism-and-genetics-its-complicated.html">my last post</a> --- <a href="http://www.sciencemag.org/cgi/content/short/316/5823/445">Sebat <em>et al</em>., 2007</a> (full text <a href="http://intramural.nimh.nih.gov/pdn/pubs/pub-22.pdf">here</a>) --- the authors report finding a spontaneous deletion of the first coding region of <em>SLC4A10</em> in a pair of twin girls with autism.</span><br />
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<span style="font-family: Trebuchet MS;">There is also a <a href="http://archneur.ama-assn.org/cgi/content/full/65/4/550">recent report</a> of a girl with epilepsy and intellectual disability having part of this gene --- a 48,000-base stretch of the 2q24 region falling between coding regions 2 and 3 of <em>SLC4A10</em> --- moved to another chromosome: chromosome 13.</span><br />
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<span style="font-family: Trebuchet MS;"><strong>How do these mutations affect protein function?</strong> </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Mice bred with the entire <em>SLC4A10</em> gene missing were found to have much smaller brain ventricles than normal mice, and also had altered <a href="http://en.wikipedia.org/wiki/Choroid_plexus">choroid plexus</a> tissue. (The choroid plexus is where cerebrospinal fluid is made and waste is filtered out of it; active-transport proteins are especially dense there). Researchers found it harder to induce seizures in these mice as compared with normal mice using the proconvulsant (i.e., seizure-inducing) drugs <a href="http://en.wikipedia.org/wiki/Pentylenetetrazol">pentylenetetrazole</a> and <a href="http://en.wikipedia.org/wiki/Pilocarpine">pilocarpine</a>. </span><br />
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<span style="font-family: trebuchet ms;"></span>
<span style="font-family: trebuchet ms;">Neither of the mutations observed in humans involves knocking out the entire gene; one involves deleting the first (of twenty-six) coding region, and the other involves switching a fairly long non-coding region with a sequence from another chromosome. Nothing is deleted in that case, but the insertion of something random into the middle of a gene might derail the process of assembling a working protein using that gene's (garbled) instructions. So both mutations impair the production of this protein to an unknown degree --- the protein probably isn't completely absent, but it might be present in reduced quantities or truncated, less-than-fully-functional form.</span><br />
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<span style="font-family: Trebuchet MS;"><strong>How common are they?</strong></span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Very rare. Mutations in this gene are probably only a factor for a tiny, tiny minority of autistic people, whom I would suspect also have seizures. </span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>Database entries for this gene</strong>: <a href="http://autism.mindspec.org/humangene/detail/SLC4A10">AutDB</a>, <a href="http://www.ncbi.nlm.nih.gov/gene/57282">Entrez Gene</a>, <a href="http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000144290;r=2:162280843-162841792">Ensembl</a>, <a href="http://genatlas.medecine.univ-paris5.fr/fiche.php?n=10127">Genatlas</a>, <a href="http://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC4A10">GeneCards</a>, <a href="http://gene.sfari.org/humangene/detail/SLC4A10">SFARI Gene</a></span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>Sources:</strong></span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Biological+Chemistry&rft_id=info%3Adoi%2F10.1074%2Fjbc.M110.108712&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Na%2B-dependent+HCOFormula+Import+by+the+slc4a10+Gene+Product+Involves+Cl-+Export&rft.issn=0021-9258&rft.date=2010&rft.volume=285&rft.issue=35&rft.spage=26998&rft.epage=27007&rft.artnum=http%3A%2F%2Fwww.jbc.org%2Fcgi%2Fdoi%2F10.1074%2Fjbc.M110.108712&rft.au=Damkier%2C+H.&rft.au=Aalkjaer%2C+C.&rft.au=Praetorius%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Genetics+%2C+Cell+Biology%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Biological+Chemistry&rft_id=info%3Adoi%2F10.1074%2Fjbc.M110.108712&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Na%2B-dependent+HCOFormula+Import+by+the+slc4a10+Gene+Product+Involves+Cl-+Export&rft.issn=0021-9258&rft.date=2010&rft.volume=285&rft.issue=35&rft.spage=26998&rft.epage=27007&rft.artnum=http%3A%2F%2Fwww.jbc.org%2Fcgi%2Fdoi%2F10.1074%2Fjbc.M110.108712&rft.au=Damkier%2C+H.&rft.au=Aalkjaer%2C+C.&rft.au=Praetorius%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Genetics+%2C+Cell+Biology%2C+Molecular+Biology">Damkier, H., Aalkjaer, C., & Praetorius, J. (2010). Na+-dependent HCOFormula Import by the slc4a10 Gene Product Involves Cl- Export <span style="font-style: italic;">Journal of Biological Chemistry, 285</span> (35), 26998-27007 DOI: <a href="http://dx.doi.org/10.1074/jbc.M110.108712" rev="review">10.1074/jbc.M110.108712</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Archives+of+neurology&rft_id=info%3Apmid%2F18413482&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Disruption+of+sodium+bicarbonate+transporter+SLC4A10+in+a+patient+with+complex+partial+epilepsy+and+mental+retardation.&rft.issn=0003-9942&rft.date=2008&rft.volume=65&rft.issue=4&rft.spage=550&rft.epage=553&rft.artnum=http%3A%2F%2Farchneur.ama-assn.org%2Fcgi%2Fcontent%2Ffull%2F65%2F4%2F550&rft.au=Gurnett+CA&rft.au=Veile+R&rft.au=Zempel+J&rft.au=Blackburn+L&rft.au=Lovett+M&rft.au=Bowcock+A&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics"><br /></span></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Archives+of+neurology&rft_id=info%3Apmid%2F18413482&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Disruption+of+sodium+bicarbonate+transporter+SLC4A10+in+a+patient+with+complex+partial+epilepsy+and+mental+retardation.&rft.issn=0003-9942&rft.date=2008&rft.volume=65&rft.issue=4&rft.spage=550&rft.epage=553&rft.artnum=http%3A%2F%2Farchneur.ama-assn.org%2Fcgi%2Fcontent%2Ffull%2F65%2F4%2F550&rft.au=Gurnett+CA&rft.au=Veile+R&rft.au=Zempel+J&rft.au=Blackburn+L&rft.au=Lovett+M&rft.au=Bowcock+A&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics">Gurnett CA, Veile R, Zempel J, Blackburn L, Lovett M, & Bowcock A (2008). Disruption of sodium bicarbonate transporter SLC4A10 in a patient with complex partial epilepsy and mental retardation. <span style="font-style: italic;">Archives of neurology, 65</span> (4), 550-553 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/18413482" rev="review">18413482</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences&rft_id=info%3Adoi%2F10.1073%2Fpnas.0705487105&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Mice+with+targeted+Slc4a10+gene+disruption+have+small+brain+ventricles+and+show+reduced+neuronal+excitability&rft.issn=0027-8424&rft.date=2008&rft.volume=105&rft.issue=1&rft.spage=311&rft.epage=316&rft.artnum=http%3A%2F%2Fwww.pnas.org%2Fcgi%2Fdoi%2F10.1073%2Fpnas.0705487105&rft.au=Jacobs%2C+S.&rft.au=Ruusuvuori%2C+E.&rft.au=Sipila%2C+S.&rft.au=Haapanen%2C+A.&rft.au=Damkier%2C+H.&rft.au=Kurth%2C+I.&rft.au=Hentschke%2C+M.&rft.au=Schweizer%2C+M.&rft.au=Rudhard%2C+Y.&rft.au=Laatikainen%2C+L.&rft.au=Tyynela%2C+J.&rft.au=Praetorius%2C+J.&rft.au=Voipio%2C+J.&rft.au=Hubner%2C+C.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Genetics"><br /></span></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences&rft_id=info%3Adoi%2F10.1073%2Fpnas.0705487105&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Mice+with+targeted+Slc4a10+gene+disruption+have+small+brain+ventricles+and+show+reduced+neuronal+excitability&rft.issn=0027-8424&rft.date=2008&rft.volume=105&rft.issue=1&rft.spage=311&rft.epage=316&rft.artnum=http%3A%2F%2Fwww.pnas.org%2Fcgi%2Fdoi%2F10.1073%2Fpnas.0705487105&rft.au=Jacobs%2C+S.&rft.au=Ruusuvuori%2C+E.&rft.au=Sipila%2C+S.&rft.au=Haapanen%2C+A.&rft.au=Damkier%2C+H.&rft.au=Kurth%2C+I.&rft.au=Hentschke%2C+M.&rft.au=Schweizer%2C+M.&rft.au=Rudhard%2C+Y.&rft.au=Laatikainen%2C+L.&rft.au=Tyynela%2C+J.&rft.au=Praetorius%2C+J.&rft.au=Voipio%2C+J.&rft.au=Hubner%2C+C.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Genetics">Jacobs, S., Ruusuvuori, E., Sipila, S., Haapanen, A., Damkier, H., Kurth, I., Hentschke, M., Schweizer, M., Rudhard, Y., Laatikainen, L., Tyynela, J., Praetorius, J., Voipio, J., & Hubner, C. (2008). Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability <span style="font-style: italic;">Proceedings of the National Academy of Sciences, 105</span> (1), 311-316 DOI: <a href="http://dx.doi.org/10.1073/pnas.0705487105" rev="review">10.1073/pnas.0705487105</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="Strong+Association+of+De+Novo+Copy+Number+Mutations+with+Autism&rft.issn=" au="Ye%2C+K.&rft.au=" class="Z3988" date="2007&rft.volume=" epage="449&rft.artnum=" issue="5823&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1126%2Fscience.1138659&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Biology%2CMedicine%2CGenetics" title="ctx_ver="><br /></span></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="Strong+Association+of+De+Novo+Copy+Number+Mutations+with+Autism&rft.issn=" au="Ye%2C+K.&rft.au=" class="Z3988" date="2007&rft.volume=" epage="449&rft.artnum=" issue="5823&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1126%2Fscience.1138659&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Biology%2CMedicine%2CGenetics" title="ctx_ver=">Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y., Hicks, J., Spence, S., Lee, A., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P., Bregman, J., Sutcliffe, J., Jobanputra, V., Chung, W., Warburton, D., King, M., Skuse, D., Geschwind, D., Gilliam, T., Ye, K., & Wigler, M. (2007). Strong Association of De Novo Copy Number Mutations with Autism <span style="font-style: italic;">Science, 316</span> (5823), 445-449 DOI: <a href="http://dx.doi.org/10.1126/science.1138659" rev="review">10.1126/science.1138659</a></span></span> Lindsayhttp://www.blogger.com/profile/10860246538349067232noreply@blogger.com0tag:blogger.com,1999:blog-5760145767660787785.post-33829584700242241162016-01-14T15:19:00.003-08:002016-01-14T15:19:45.957-08:00Gene Spotlight: CNTNAP2<div align="left">
<span style="font-family: trebuchet ms;">(Cross-posted from <a href="http://autistscorner.blogspot.com/2010/11/autism-related-gene-spotlight-cntnap2.html">my other blog</a>)</span><br />
<span style="font-family: trebuchet ms;"><em><strong><br /></strong></em></span>
<span style="font-family: trebuchet ms;"><em><strong>EXECUTIVE SUMMARY</strong>: CNTNAP2 is a large gene near the end of chromosome 7 that encodes a cell-adhesion protein involved in distributing ion channels along axons (the long tails of nerve cells) and in attaching the fatty cells making up the myelin sheath to the surface of the axon. DIsruptions in this gene have been associated with autism, epilepsy, Tourette syndrome and other neurodevelopmental disorders. Variations at certain points within the gene that don't alter or disrupt its expression have also been associated with an increased likelihood of autism.</em></span></div>
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<span style="font-family: Trebuchet MS;">__________________________________________________________________________</span></div>
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<strong><span style="font-family: trebuchet ms;"><br /></span></strong>
<strong><span style="font-family: trebuchet ms;">Where is it?</span></strong><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Chromosome 7, in the 7q35 region (i.e., near the end of the long, lower arm of chromosome 7).<img alt="" border="0" id="BLOGGER_PHOTO_ID_5539879179851922994" src="http://2.bp.blogspot.com/_CGQTWjODmZw/TOGawzWn_jI/AAAAAAAAAj8/pp2FdqY4jXM/s400/CNTNAP2%2Blocation%2B-%2Bchromosome%2B7.jpg" style="cursor: hand; display: block; height: 171px; margin: 0px auto 10px; text-align: center; width: 400px;" /></span></div>
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<span style="font-family: Trebuchet MS;"><em>CNTNAP2</em> is, according to Entrez Gene, one of the largest single genes in the human genome; it's about 2.3 million base pairs long, taking up 1.5% of the total space on chromosome 7.</span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>What does it do?</strong></span><br />
<span style="font-family: Trebuchet MS;"><em><br /></em></span>
<span style="font-family: Trebuchet MS;"><em>CNTNAP2</em> encodes a cell-adhesion protein called contactin-associated protein-like 2 (Caspr2), which is part of a superfamily of adhesion proteins specific to nerve cells called neurexins.</span><br />
<br />
<span style="font-family: Trebuchet MS;">During development, Caspr2 plays an important role in organizing the long tail of the neuron, called the axon. Caspr2 directs certain types of <a href="http://en.wikipedia.org/wiki/Voltage-gated_potassium_channel">voltage-gated potassium ion channels</a> (i.e., channels that open or close in reponse to changes in membrane potential) to insert themselves into the axon's membrane at specific intervals; it also forms part of the junction between the axon and the fatty <a href="http://en.wikipedia.org/wiki/Glial_cell">glial cells</a> that form the <a href="http://en.wikipedia.org/wiki/Myelin">myelin sheath</a> around the axon, which both <a href="http://en.wikipedia.org/wiki/Insulator_(electrical)">insulates</a> the axon (like the rubber tubing around a wire insulates the wire) and allows the electrical current to travel faster, in a discontinuous, hopping ("<a href="http://en.wikipedia.org/wiki/Saltatory_conduction">saltatory</a>") manner from node to node along the myelinated axon. </span><span style="font-family: trebuchet ms;"><em><span style="font-size: 85%;">
</span></em></span></div>
<img alt="" border="0" id="BLOGGER_PHOTO_ID_5541121227406061538" src="http://4.bp.blogspot.com/_CGQTWjODmZw/TOYEZfDqL-I/AAAAAAAAAkM/eFBWGv1zkzQ/s400/neuron.png" style="cursor: hand; display: block; height: 215px; margin: 0px auto 10px; text-align: center; width: 400px;" /> <em><span style="font-size: 85%;"><span style="font-family: trebuchet ms;"></span></span></em>
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<div align="center">
<em><span style="font-size: 85%;"><span style="font-family: trebuchet ms;">(Image adapted from </span></span></em><em><span style="font-size: 85%;"><a href="http://en.wikipedia.org/wiki/Neuron"><span style="font-family: trebuchet ms;">Wikipedia</span></a><span style="font-family: trebuchet ms;">)</span></span></em> </div>
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">To allow the current to travel discontinuously, the fatty cells making up the myelin sheath leave small stretches of axon uncovered at regular intervals. These unmyelinated points are called the <a href="http://en.wikipedia.org/wiki/Node_of_Ranvier">nodes of Ranvier</a>, and it is at these nodes that Caspr2 plays its traffic-directing role.</span><span style="font-family: trebuchet ms; font-size: 85%;"> <img alt="" border="0" id="BLOGGER_PHOTO_ID_5541135058303939906" src="http://2.bp.blogspot.com/_CGQTWjODmZw/TOYQ-jKrdUI/AAAAAAAAAkU/PFs7s2ESyi0/s400/node%2Bof%2BRanvier.jpg" style="cursor: hand; display: block; height: 175px; margin: 0px auto 10px; text-align: center; width: 400px;" /></span><span style="font-family: trebuchet ms; font-size: 85%;"> </span>
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<div align="center">
<span style="font-family: trebuchet ms; font-size: 85%;"><em>(Node of Ranvier and surrounding regions; taken from Figure 4 in Poliak and Peles, 2003)</em></span></div>
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Caspr2 sits in the membrane of the axon in its juxtaparanodal region (which means, "the region right next to the region next to the node" in ScienceSpeak), where its cytoplasmic domain (the part of a membrane-spanning protein that's inside the cell) links up with potassium ion channels prior to their insertion in the membrane, and directs them to insert adjacent to the complex of adhesion proteins including Caspr2. This ensures that the potassium channels all cluster together in the juxtaparanodal region, rather than distribute themselves more or less evenly along the axon, as they would do without guidance from the adhesion proteins.</span><br />
<br />
<span style="font-family: trebuchet ms;">This superabundance of potassium ion channels near the nodes of Ranvier makes the nodes hypersensitive to membrane depolarization (which is mediated by traffic of ions, including potassium, into and out of the cell), which allows an action potential (the "firing" of a neuron that happens once it reaches a certain threshold level of membrane depolarization) to be transmitted from node to node more easily.</span><br />
<br />
<span style="font-family: trebuchet ms;">This gene may also play a role in organizing the layers of cortical tissue during development. </span><br />
<strong><span style="font-family: Trebuchet MS;"><br /></span></strong>
<strong><span style="font-family: Trebuchet MS;">What mutant versions of this gene have been discovered?</span></strong><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Lots of different ones! Here are (some of) the mutations that have been described so far:</span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">An exchange of genetic material between two chromosomes: 7q35 and 15q26.2, with the breakpoint on chromosome 7 occurring inside <em>CNTNAP2</em> (in the 11th intron, or noncoding region), and the breakpoint on chromosome 15 occurring in a relatively ill-understood region that's<em> hypothesized</em> to be a gene. This translocation was found in three generations of Old Order Amish, and described in <a href="http://www.nature.com/ejhg/journal/v15/n6/full/5201824a.html">this article in the <em>European Journal of Human Genetics</em></a>. Depending on whether the translocation was balanced or not (i.e., whether there was any net gain or loss of genetic material), the people having this mutation might be completely healthy and neurotypical, or they might have severe problems and die young.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7RKV-4T0MMS3-1&_user=10&_coverDate=12%2F31%2F2008&_rdoc=17&_fmt=high&_orig=browse&_origin=browse&_zone=rslt_list_item&_srch=doc-info(%23toc%2325732%232008%23999489993%23730317%23FLA%23display%23Volume)&_cdi=25732&_sort=d&_docanchor=&_ct=26&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e653fa6a381664fd8d38292d6cba3564&searchtype=a">An autistic woman in Italy</a> was found to be missing a large (12 million base pairs!) chunk of chromosome 7q33-q36; <em>CNTNAP2</em> is contained within the deleted region.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.springerlink.com/content/yl886372552u6071/fulltext.pdf">An autistic boy in the Netherlands</a> was found to have an <a href="http://en.wikipedia.org/wiki/Chromosomal_inversion">inversion</a> --- a break in the q arm of one of his copies of chromosome 7 that reversed the sequence of genes on the broken part when it repaired itself --- between regions 7q32.1 and 7q35. Parts of CNTNAP2 --- the promoter region, which is where the enzymes involved in DNA transcription (the first stage of gene expression) attach to the genome and begin transcription, and parts of intron 1 and exon 2, which also contain important regulatory sites --- have been moved to another chromosome entirely: chromosome 1q31.2.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253974/">A preschool-aged boy with seizures and autistic traits</a> (but not enough to be diagnosed with an ASD) was found to have an inversion between regions 7q11.22 and 7q35. The break in 7q35 occurs within CNTNAP2, somewhere between exons 10 and 13. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Nine of eighteen Old Order Amish people with developmental disabilities and a childhood-onset form of epilepsy were found to have <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa052773?hits=10&andorexactfulltext=and&FIRSTINDEX=440&FIRSTINDEX=440&SEARCHID=1&searchid=1&COLLECTION_NUM=16&resourcetype=HWCIT&resourcetype=HWCIT&andorexacttitleabs=and#t=article">a deletion of a single nucleotide</a> (#3709) in coding region 22 of <em>CNTNAP2</em>. The deletion was present in both copies of the gene.</span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">A family in which several members (the father and both children) have <a href="http://www.ncbi.nlm.nih.gov/sites/entrez/12809671?dopt=Abstract&holding=f1000,f1000m,isrctn">Tourette syndrome, obsessive-compulsive disorder, or both</a>, were found to have a complex rearrangement of genes on chromosomes 2 and 7, including some swapping of parts of genes between those two chromosomes. Among other things, part of a gene on chromosome 2 is inserted into<em> CNTNAP2</em>, in a noncoding region. The inserted part is very large (12 million bases, six times the size of <em>CNTNAP2</em> itself). </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">In </span><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253968/"><span style="font-family: trebuchet ms;">a fairly large sample of families</span></a><span style="font-family: trebuchet ms;"> including more than one autistic member, a </span><a href="http://www.snpedia.com/index.php/Rs7794745"><span style="font-family: trebuchet ms;">single-nucleotide change</span></a><span style="font-family: trebuchet ms;"> --- a substitution of thymine for adenine --- at a position approximately one-quarter of the way between coding regions 2 and 3 of <em>CNTNAP2</em> (in other words, in an intron, or noncoding region) was found to occur at somewhat higher rates in autistic children than in their nonautistic siblings. This was especially true if the mutation was inherited from the mother.</span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">A study of <a href="http://www.ncbi.nlm.nih.gov/pubmed/20414140?dopt=Abstract">185 Han Chinese families</a> found another single-nucleotide variation in a noncoding region of CNTNAP2 that's associated with an increased likelihood of having autism. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">A study of families participating in the Autism Genetic Resource Exchange found several single-nucleotide changes near the end of the intron between exons (coding regions) 13 and 14 in <em>CNTNAP2</em>, where the presence of a variant nucleotide at one of four different positions (with variation at one site in particular, designated </span><a href="http://www.snpedia.com/index.php/Rs2710102"><span style="font-family: trebuchet ms;">rs2710102</span></a><span style="font-family: trebuchet ms;">, seeming to drive variation at the other three) was associated with delays in development of speech.</span><br />
<br />
<span style="font-family: trebuchet ms;"></span>
<span style="font-family: trebuchet ms;"><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775834/">Three people (two of them siblings) who had undergone genetic testing</a> for a separate mutation (in a gene called <em>TCF4</em>, the underexpression of which causes <a href="http://www.chromosome18.org/Conditions/PittHopkinssyndrome/tabid/726/Default.aspx">Pitt-Hopkins syndrome</a>) were found to have deletions in <em>CNTNAP2</em>; the two siblings were missing exons 2-9, and the other person was missing exons 5-8, and had another mutation rendering a splice site (a place where various enzymes cut out those parts of a transcribed gene that are not needed in protein synthesis, and then join the remaining fragments back together) potentially invisible to splicing enzymes, which could mean that exon 10, also, has been functionally deleted. </span><br />
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><img alt="" border="0" height="160" id="BLOGGER_PHOTO_ID_5544030727282193170" src="http://2.bp.blogspot.com/_CGQTWjODmZw/TPBakquBcxI/AAAAAAAAAk0/U-K3fX-SlxU/s640/CNTNAP2%2Bexons.jpg" style="display: block; margin: 0px auto 10px; text-align: center;" width="640" /></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Trebuchet MS, sans-serif;">Domain map of CNTNAP2, reproduced from Zweier <i>et al.</i>, 2009</span></td></tr>
</tbody></table>
<strong><span style="font-family: Trebuchet MS;"></span></strong><br />
<strong><span style="font-family: Trebuchet MS;"></span></strong>
<strong><span style="font-family: Trebuchet MS;">How do these mutations affect protein function?</span></strong>
<span style="font-size: 0;"><span style="font-family: trebuchet ms;"><span style="font-size: 85%;"></span></span></span>
<br />
<div align="center">
<div style="text-align: left;">
<span style="font-size: 0;"><span style="font-family: trebuchet ms;"><span style="font-size: 85%;"><em>(Drawing of CNTNAP2 exons and the protein domains they encode taken from <a href="http://www.ncbi.nlm.nih.gov/pubmed/19896112">Zweier et al., 2009</a>)</em></span></span></span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">A mutation's effect on protein function depends on where it is in the gene. The color-coded map I posted at the top of this section shows what kind of protein domain each coding region of <em>CNTNAP2</em> encodes, and what role each domain plays in the protein's overall function (to the extent that either of those things is known, which can vary a lot from gene to gene).</span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">For instance, the deletions mentioned in <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775834/">this article</a> --- exons 5-8 in one person, and exons 2-9 in the others --- include a large block of laminin G domains (exons 5-10) and all three of the discoidin-like (DISC) domains near the end of the (exons 2-4). </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Both of these groups are on the part of Caspr2 that reaches outside the cell, and are involved in binding to other proteins on other cells to join the two cells together. In the nervous system, the two types of cells likeliest to be joined together are neurons and glial cells, during myelination.</span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Another domain that's important to Caspr2 function is the PDZ-binding domain at the end of the cytoplasmic half of the protein. That domain binds to <a href="http://en.wikipedia.org/wiki/PDZ_(biology)">PDZ domains</a> on potassium channels while they're free in the cytoplasm and guide them to embed in the cell membrane near Caspr2. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">The point mutation described in <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa052773">this article</a> would lead to garbled (or non-)expression of exons 23 and 24, which encode the transmembrane domain (i.e., the part of the protein that is embedded in the cell membrane) and the PDZ-binding domain; absence of those domains from Caspr2 might prevent that protein from clustering the potassium channels near the node of Ranvier. </span></div>
<div style="text-align: left;">
<strong><span style="font-family: Trebuchet MS;"><br /></span></strong></div>
<div style="text-align: left;">
<span style="font-family: trebuchet ms;"><strong></strong></span><strong><span style="font-family: Trebuchet MS;">How common are they?</span></strong> </div>
<div style="text-align: left;">
<span style="font-family: trebuchet ms;"><br /></span></div>
<div style="text-align: left;">
<span style="font-family: trebuchet ms;">Most of the mutations described above --- the deletions and translocations --- are very rare, possibly even unique to the individuals or families in whom they were discovered.</span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">However, some of the single-nucleotide polymorphisms (SNPs) --- the alteration of a single nucleotide base --- are fairly common. The polymorphism described in <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253968/">this article</a>, the presence of thymine at a point in a noncoding region of <em>CNTNAP2</em> where most people have adenine, is thought to occur in 36% of people. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">So, while those variant alleles might be somewhat more common in people with autism than in people without it, there will still be lots of people without autism who also have those genotypes. The prevalence of autism being what it is, there are probably a lot more neurotypical people with a given polymorphism than there are autistic (or otherwise non-neurotypical) people. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">(<a href="http://biorxiv.org/content/biorxiv/early/2015/12/20/034363.full.pdf">This article from 2015</a> describes an extended family in Italy who share a homozygous -- present on both copies of chromosome 7 -- deletion spanning exons 2 and 3 of <i>CNTN</i></span><span style="font-family: 'trebuchet ms';"><i>AP2</i>; everyone in the family who possessed this deletion displayed a range of similar neurodevelopmental disabilities. The authors of the article say that, while heterozygous mutations in <i>CNTNAP2</i> are common and frequently have no effect on development, homozygous mutations are much rarer and are always accompanied by some obvious disruption of neurological development.)</span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>Database entries for this gene:</strong> <a href="http://autism.mindspec.org/humangene/detail/CNTNAP2">AutDB</a>, <a href="http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000174469;r=7:145813453-148118090">Ensembl</a>, <a href="http://www.ncbi.nlm.nih.gov/gene/26047">Entrez Gene</a>, <a href="http://www.genecards.org/cgi-bin/carddisp.pl?gene=CNTNAP2">GeneCards</a>, <a href="http://www.labome.org/gene/human/cntnap2-26047.html">Labome.org</a>, <a href="http://lovd.bx.psu.edu/home.php?select_db=CNTNAP2">Leiden Open Variation Database</a> </span><br />
<strong><span style="font-family: Trebuchet MS;"><br /></span></strong>
<strong><span style="font-family: Trebuchet MS;">Sources:</span></strong><br />
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+Journal+of+Human+Genetics&rft_id=info%3Adoi%2F10.1016%2Fj.ajhg.2007.09.015&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+Common+Genetic+Variant+in+the+Neurexin+Superfamily+Member+CNTNAP2+Increases+Familial+Risk+of+Autism&rft.issn=00029297&rft.date=2008&rft.volume=82&rft.issue=1&rft.spage=160&rft.epage=164&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0002929707000213&rft.au=Arking%2C+D.&rft.au=Cutler%2C+D.&rft.au=Brune%2C+C.&rft.au=Teslovich%2C+T.&rft.au=West%2C+K.&rft.au=Ikeda%2C+M.&rft.au=Rea%2C+A.&rft.au=Guy%2C+M.&rft.au=Lin%2C+S.&rft.au=Cook+Jr.%2C+E.&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics"><br /></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+Journal+of+Human+Genetics&rft_id=info%3Adoi%2F10.1016%2Fj.ajhg.2007.09.015&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=A+Common+Genetic+Variant+in+the+Neurexin+Superfamily+Member+CNTNAP2+Increases+Familial+Risk+of+Autism&rft.issn=00029297&rft.date=2008&rft.volume=82&rft.issue=1&rft.spage=160&rft.epage=164&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0002929707000213&rft.au=Arking%2C+D.&rft.au=Cutler%2C+D.&rft.au=Brune%2C+C.&rft.au=Teslovich%2C+T.&rft.au=West%2C+K.&rft.au=Ikeda%2C+M.&rft.au=Rea%2C+A.&rft.au=Guy%2C+M.&rft.au=Lin%2C+S.&rft.au=Cook+Jr.%2C+E.&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics">Arking, D., Cutler, D., Brune, C., Teslovich, T., West, K., Ikeda, M., Rea, A., Guy, M., Lin, S., & Cook Jr., E. (2008). A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Increases Familial Risk of Autism <span style="font-style: italic;">The American Journal of Human Genetics, 82</span> (1), 160-164 DOI: <a href="http://dx.doi.org/10.1016/j.ajhg.2007.09.015" rev="review">10.1016/j.ajhg.2007.09.015</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><br /></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+American+Journal+of+Human+Genetics&rft_id=info%3Adoi%2F10.1016%2Fj.ajhg.2007.09.017&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Molecular+Cytogenetic+Analysis+and+Resequencing+of+Contactin+Associated+Protein-Like+2+in+Autism+Spectrum+Disorders&rft.issn=00029297&rft.date=2008&rft.volume=82&rft.issue=1&rft.spage=165&rft.epage=173&rft.artnum=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0002929707000237&rft.au=Bakkaloglu%2C+B.&rft.au=O%27Roak%2C+B.&rft.au=Louvi%2C+A.&rft.au=Gupta%2C+A.&rft.au=Abelson%2C+J.&rft.au=Morgan%2C+T.&rft.au=Chawarska%2C+K.&rft.au=Klin%2C+A.&rft.au=Ercan-Sencicek%2C+A.&rft.au=Stillman%2C+A.&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics">Bakkaloglu, B., O'Roak, B., Louvi, A., Gupta, A., Abelson, J., Morgan, T., Chawarska, K., Klin, A., Ercan-Sencicek, A., & Stillman, A. (2008). Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders <span style="font-style: italic;">The American Journal of Human Genetics, 82</span> (1), 165-173 DOI: <a href="http://dx.doi.org/10.1016/j.ajhg.2007.09.017" rev="review">10.1016/j.ajhg.2007.09.017</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><br /></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="Disruption+of+the+CNTNAP2+gene+in+a+t%287%3B15%29+translocation+family+without+symptoms+of+Gilles+de+la+Tourette+syndrome&rft.issn=" au="T%C3%BCmer%2C+Z.&rfe_dat=" class="Z3988" date="2007&rft.volume=" epage="713&rft.artnum=" included="0;bpr3.tags=" issue="6&rft.spage=" rft_id="info%3Adoi%2F10.1038%2Fsj.ejhg.5201824&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" title="ctx_ver=">Belloso, J., Bache, I., Guitart, M., Caballin, M., Halgren, C., Kirchhoff, M., Ropers, H., Tommerup, N., & Tümer, Z. (2007). Disruption of the CNTNAP2 gene in a t(7;15) translocation family without symptoms of Gilles de la Tourette syndrome <span style="font-style: italic;">European Journal of Human Genetics, 15</span> (6), 711-713 DOI: <a href="http://dx.doi.org/10.1038/sj.ejhg.5201824" rev="review">10.1038/sj.ejhg.5201824</a></span> </span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><br /></span>
<span class="Z3988" style="font-family: Trebuchet MS, sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neuron&rft_id=info%3Apmid%2F10624965&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Caspr2%2C+a+new+member+of+the+neurexin+superfamily%2C+is+localized+at+the+juxtaparanodes+of+myelinated+axons+and+associates+with+K%2B+channels.&rft.issn=0896-6273&rft.date=1999&rft.volume=24&rft.issue=4&rft.spage=1037&rft.epage=47&rft.artnum=&rft.au=Poliak+S&rft.au=Gollan+L&rft.au=Martinez+R&rft.au=Custer+A&rft.au=Einheber+S&rft.au=Salzer+JL&rft.au=Trimmer+JS&rft.au=Shrager+P&rft.au=Peles+E&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CCell+Biology%2C+Molecular+Biology%2C+Neurology">Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, Trimmer JS, Shrager P, & Peles E (1999). Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. <span style="font-style: italic;">Neuron, 24</span> (4), 1037-47 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/10624965" rev="review">10624965</a></span><br />
<span class="Z3988" style="font-family: Trebuchet MS, sans-serif;" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Reviews+Neuroscience&rft_id=info%3Adoi%2F10.1038%2Fnrn1253&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+local+differentiation+of+myelinated+axons+at+nodes+of+Ranvier&rft.issn=1471-003X&rft.date=2003&rft.volume=4&rft.issue=12&rft.spage=968&rft.epage=980&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnrn1253&rft.au=Poliak%2C+S.&rft.au=Peles%2C+E.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CCell+Biology%2C+Molecular+Biology%2C+Neurology"><br /></span>
<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+Reviews+Neuroscience&rft_id=info%3Adoi%2F10.1038%2Fnrn1253&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=The+local+differentiation+of+myelinated+axons+at+nodes+of+Ranvier&rft.issn=1471-003X&rft.date=2003&rft.volume=4&rft.issue=12&rft.spage=968&rft.epage=980&rft.artnum=http%3A%2F%2Fwww.nature.com%2Fdoifinder%2F10.1038%2Fnrn1253&rft.au=Poliak%2C+S.&rft.au=Peles%2C+E.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CCell+Biology%2C+Molecular+Biology%2C+Neurology">Poliak, S., & Peles, E. (2003). The local differentiation of myelinated axons at nodes of Ranvier <span style="font-style: italic;">Nature Reviews Neuroscience, 4</span> (12), 968-980 DOI: <a href="http://dx.doi.org/10.1038/nrn1253" rev="review">10.1038/nrn1253</a></span> </span><br />
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<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="Disruption+of+CNTNAP2+and+additional+structural+genome+changes+in+a+boy+with+speech+delay+and+autism+spectrum+disorder&rft.issn=" au="Holder%2C+S.&rft.au=" class="Z3988" date="2009&rft.volume=" epage="89&rft.artnum=" issue="1&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1007%2Fs10048-009-0205-1&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Medicine%2CGenetics" title="ctx_ver=">Poot, M., Beyer, V., Schwaab, I., Damatova, N., Slot, R., Prothero, J., Holder, S., & Haaf, T. (2009). Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder <span style="font-style: italic;">neurogenetics, 11</span> (1), 81-89 DOI: <a href="http://dx.doi.org/10.1007/s10048-009-0205-1" rev="review">10.1007/s10048-009-0205-1</a></span> </span><br />
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<span style="font-family: Trebuchet MS, sans-serif;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=BioRxiv&rft_id=info%3Adoi%2F10.1101%2F034363&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Characterisation+of+CASPR2+deficiency+disorder+-+a+syndrome+involving+autism%2C+epilepsy%2C+and+language+impairment&rft.issn=&rft.date=2015&rft.volume=&rft.issue=&rft.spage=&rft.epage=&rft.artnum=&rft.au=Rodenas-Cuadrado+P.&rft.au=Pietrafusa+N.&rft.au=Francavilla+T.&rft.au=La+Neve+A.&rft.au=Striano+P.&rft.au=Vernes+S.+C.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CGenetics">Rodenas-Cuadrado P., Pietrafusa N., Francavilla T., La Neve A., Striano P., & Vernes S. C. (2015). Characterisation of CASPR2 deficiency disorder - a syndrome involving autism, epilepsy, and language impairment <span style="font-style: italic;">BioRxiv</span> DOI: <a href="http://dx.doi.org/10.1101/034363" rev="review">10.1101/034363</a></span>
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<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="A+12Mb+deletion+at+7q33%E2%80%93q35+associated+with+autism+spectrum+disorders+and+primary+amenorrhea&rft.issn=" au="TONIOLO%2C+D.&rft.au=" class="Z3988" date="2008&rft.volume=" epage="638&rft.artnum=" issue="6&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1016%2Fj.ejmg.2008.06.010&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Medicine%2CGenetics" title="ctx_ver="><br /></span></span><br />
<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="A+12Mb+deletion+at+7q33%E2%80%93q35+associated+with+autism+spectrum+disorders+and+primary+amenorrhea&rft.issn=" au="TONIOLO%2C+D.&rft.au=" class="Z3988" date="2008&rft.volume=" epage="638&rft.artnum=" issue="6&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1016%2Fj.ejmg.2008.06.010&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Medicine%2CGenetics" title="ctx_ver=">ROSSI, E., VERRI, A., PATRICELLI, M., DESTEFANI, V., RICCA, I., VETRO, A., CICCONE, R., GIORDA, R., TONIOLO, D., & MARASCHIO, P. (2008). A 12Mb deletion at 7q33–q35 associated with autism spectrum disorders and primary amenorrhea <span style="font-style: italic;">European Journal of Medical Genetics, 51</span> (6), 631-638 DOI: <a href="http://dx.doi.org/10.1016/j.ejmg.2008.06.010" rev="review">10.1016/j.ejmg.2008.06.010</a></span> </span><br />
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<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="Recessive+symptomatic+focal+epilepsy+and+mutant+contactin-associated+protein-like+2.&rft.issn=" au="Strauss+KA&rft.au=" class="Z3988" date="2006&rft.volume=" epage="7&rft.artnum=" issue="13&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Apmid%2F16571880&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Medicine%2CGenetics" title="ctx_ver=">Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, & Morton DH (2006). Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. <span style="font-style: italic;">The New England journal of medicine, 354</span> (13), 1370-7 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/16571880" rev="review">16571880</a></span> </span><br />
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<span style="font-family: Trebuchet MS, sans-serif;"><span atitle="CNTNAP2+is+disrupted+in+a+family+with+Gilles+de+la+Tourette+syndrome+and+obsessive+compulsive+disorder.&rft.issn=" au="Tourette+Syndrome+Association+International+Consortium+for+Genetics&rfe_dat=" class="Z3988" date="2003&rft.volume=" epage="9&rft.artnum=" included="0;bpr3.tags=" issue="1&rft.spage=" rft_id="info%3Apmid%2F12809671&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" title="ctx_ver=">Verkerk AJ, Mathews CA, Joosse M, Eussen BH, Heutink P, Oostra BA, & Tourette Syndrome Association International Consortium for Genetics (2003). CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. <span style="font-style: italic;">Genomics, 82</span> (1), 1-9 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/12809671" rev="review">12809671</a></span> </span><br />
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<span atitle="CNTNAP2+and+NRXN1+Are+Mutated+in+Autosomal-Recessive+Pitt-Hopkins-like+Mental+Retardation+and+Determine+the+Level+of+a+Common+Synaptic+Protein+in+Drosophila&rft.issn=" au="Ekici%2C+A.&rft.au=" class="Z3988" date="2009&rft.volume=" epage="666&rft.artnum=" issue="5&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Adoi%2F10.1016%2Fj.ajhg.2009.10.004&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" style="font-family: Trebuchet MS, sans-serif;" tags="Biology%2CMedicine%2CCell+Biology%2C+Molecular+Biology%2C+Genetics" title="ctx_ver=">Zweier, C., de Jong, E., Zweier, M., Orrico, A., Ousager, L., Collins, A., Bijlsma, E., Oortveld, M., Ekici, A., & Reis, A. (2009). CNTNAP2 and NRXN1 Are Mutated in Autosomal-Recessive Pitt-Hopkins-like Mental Retardation and Determine the Level of a Common Synaptic Protein in Drosophila <span style="font-style: italic;">The American Journal of Human Genetics, 85</span> (5), 655-666 DOI: <a href="http://dx.doi.org/10.1016/j.ajhg.2009.10.004" rev="review">10.1016/j.ajhg.2009.10.004</a></span></div>
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Lindsayhttp://www.blogger.com/profile/10860246538349067232noreply@blogger.com0tag:blogger.com,1999:blog-5760145767660787785.post-30347456302114331352016-01-14T14:29:00.000-08:002016-01-14T14:29:04.048-08:00Gene Spotlight: MECP2<span style="font-family: trebuchet ms;"><i>(Cross-posted from <a href="http://autistscorner.blogspot.com/2011/07/autism-related-gene-spotlight-mecp2.html">my other blog</a>)</i></span><br />
<strong><span style="font-family: trebuchet ms;"><br /></span></strong>
<strong><span style="font-family: trebuchet ms;">Where is it?</span></strong><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Near the very end of </span><span style="font-family: trebuchet ms;">the X chromosome, at Xq28.</span>
<img alt="" border="0" id="BLOGGER_PHOTO_ID_5545552994754742946" src="http://2.bp.blogspot.com/_CGQTWjODmZw/TPXDES91yqI/AAAAAAAAAmk/sx44HYhwM0U/s400/X%2Bchromosome.jpg" style="display: block; margin: 0px auto 10px; text-align: center;" /><span style="font-family: trebuchet ms;">Here is a picture of its position relative to some other genes at that part of the X chromosome:</span>
<img alt="" border="0" id="BLOGGER_PHOTO_ID_5545552212474363346" src="http://1.bp.blogspot.com/_CGQTWjODmZw/TPXCWwvqfdI/AAAAAAAAAmc/dz8Rjl7UIbQ/s400/X%2Bchromosome%2B-%2Btail%2Bend.jpg" style="display: block; height: 103px; margin: 0px auto 10px; text-align: center; width: 400px;" /><span style="font-family: trebuchet ms;">You can see that it's not the last gene on there, and there are quite a few known and potential genes following it, but it's really, really close to the end. That picture I just posted? With <em>MECP2</em> appearing at the far left? That's the very end of a 24-<em>page</em> image. So, based on that I feel comfortable calling <em>MECP2</em> one of the last genes on the X chromosome. </span><br />
<strong><span style="font-family: Trebuchet MS;"><br /></span></strong>
<strong><span style="font-family: Trebuchet MS;">What does it do?</span></strong><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;"><a href="http://1.bp.blogspot.com/-VGFh-8tWLi4/TiM86iPZH9I/AAAAAAAAAzE/RKlHLURtmfk/s1600/MeCP2%2Bbinding%2Bto%2BDNA.jpg"></a>It encodes a protein, MeCP2, that can bind to methylated DNA (and also to a variety of other transcription-repressing proteins) and whose function is to repress transcription of its target genes. (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443785/">More recent research has also found that it can also serve as a transcriptional activator</a>). <a href="http://nar.oxfordjournals.org/content/36/19/6035/T1.expansion.html">It has a lot of target genes</a>, and their functions vary widely; many of them are other transcription factors, and many are involved in cell-cell signaling, or in signal transduction within the cell. Overall, transcription and neurotransmission seem to be the physiological processes that the majority of MeCP2 target genes are involved with, though it is also important for nerve and muscle cell growth (and thus, needs to be expressed in different amounts at different times during development). It is highly expressed in nerve cells. It's also been found to have other functions, like RNA splicing, chromatin remodeling and DNA methylation.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><strong>What mutant versions of this gene have been discovered?</strong></span>
<span style="font-family: trebuchet ms;"><span style="font-size: 85%;"><em><img alt="" border="0" id="BLOGGER_PHOTO_ID_5630556111900306706" src="http://1.bp.blogspot.com/-eH9Swv5d-Uo/TiPA86m47RI/AAAAAAAAAzc/c2dzolhbDu8/s400/MECP2%2Bexons.jpg" style="cursor: hand; display: block; height: 158px; margin: 0px auto 10px; text-align: center; width: 400px;" />(Here's a very rough impression of where some of the more common mutations (and some less-common ones that I talk about in the next section) associated with Rett syndrome fall on a map of MECP2 coding regions. Mutations that only change an amino acid are outlined in different shades of red-orange; mutations that produce a truncated version of the MeCP2 protein are outlined in black, and indicated on the map with little stop signs. Image not drawn to scale)</em></span> </span><br />
<br />
<span style="font-family: trebuchet ms;"><a href="http://www.nature.com/ng/journal/v23/n2/full/ng1099_185.html">This 1999 article in <em>Nature Genetics</em></a> (full text <a href="http://www.biologia.ufrj.br/labs/lgpd/ensino/RETT.pdf">here</a>) describes a genetic analysis of 29 girls with <a href="http://www.ninds.nih.gov/disorders/rett/detail_rett.htm">Rett syndrome</a>* (8 of whom had a family history of the condition), which found seven <a href="http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/M/Mutations.html">point mutations</a> (changes in a single nucleotide) and one case where an extra nucleotide (thymine) was inserted into the gene, which threw off the "reading" of everything that came after, since <a href="http://www.nature.com/scitable/topicpage/ribosomes-transcription-and-translation-14120660">protein synthesis</a> depends on grouping the nucleotides into threes, and stringing together the amino acids corresponding to each sequence of three nucleotides, or "<a href="http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Codons.html">codons</a>". Changing one nucleotide to another will therefore change one amino acid in the resulting protein, while adding or subtracting a nucleotide will change every amino acid that follows. (Such "<a href="http://ghr.nlm.nih.gov/handbook/illustrations/frameshift">frameshift</a>" mutations are much more likely than point mutations to result in a nonfunctional protein). </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">They were: a substitution of cytosine for thymine at nucleotide #538; substitutions of thymine for cytosine at nucleotides #390, #471, #547, #656, #837, and #1307; and the aforementioned insertion of (an extra) thymine between nucleotides #694 and #695.</span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Another genetic analysis described in <a href="http://hmg.oxfordjournals.org/content/9/9/1377.full">a 2000 article in <em>Human Molecular Genetics</em></a> found 17 different mutations in 46 girls with Rett syndrome; these mutations included substitutions of thymine for cytosine at nucleotides #473, #502, #763, #808, #880, and #916; substitutions of guanine for cytosine at nucleotides #905 and #1038; a substitution of thymine for adenine at nucleotide #592; a substitution of cytosine for adenine at nucleotide #1461; a substitution of adenine for guanine at nucleotide #317; and a ten-nucleotide deletion starting at nucleotide #1158. Most of these mutations were in exon 3, though there were a few in exons 2 and 4 as well.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://onlinelibrary.wiley.com/doi/10.1002/humu.1182/pdf">A 2004 analysis</a> of DNA samples from 56 French women and girls with Rett syndrome found five frameshift mutations: a deletion of nucleotide #345, in exon 3; a deletion 202 nucleotides long, starting at position #895; another deletion 53 nucleotides long starting at position #1124; a deletion of 8 nucleotides and an insertion of 18 nucleotides starting at position #989; and an insertion of an AG dinucleotide after nucleotide #996. All of these last four were in exon 4. </span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.annclinlabsci.org/cgi/content/abstract/41/1/93">An article from this year</a> describes a 41-base deletion in a Korean girl with Rett syndrome; the deleted region started at nucleotide #1152, in exon 4.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.ncbi.nlm.nih.gov/pubmed/21575601">Another article from this year</a> found a substitution of thymine for cytosine at nucleotide #535 in a Tunisian girl with Rett syndrome.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.neurology.org/content/56/11/1486.short">This article</a> (full text <a href="http://biostat.mc.vanderbilt.edu/wiki/pub/Main/BonnieLaFleur/neurology_paper_IPG.pdf">here</a>) describes 17 mutations: a substitution of thymine for guanine at nucleotide #298; a substitution of adenine for guanine at nucleotide #398; a substitution of guanine for adenine at nucleotide #914; a substitution of thymine for cytosine at nucleotide #730; an insertion of (an extra) guanine after nucleotide #704; an insertion of cytosine after nucleotide #747; and multiple deletions, most of which had starting points between nucleotides 1,000 and 1,200, and all but one of which were deletions of multiple nucleotides. There was also a sequence of 137 nucleotides, starting at position #1169, that was repeated.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://www.nzma.org.nz/journal/122-1296/3634/">This 2009 genomic analysis</a> of 74 people with Rett syndrome in New Zealand turned up four new mutations, including a fairly large deletion (1,596 nucleotides) that encompassed both exons 3 and 4.</span><br />
<br />
<span style="font-family: Trebuchet MS;">There are a lot more --- the International Rett Syndrome Foundation's database of mutations associated with Rett syndrome (<a href="http://mecp2.chw.edu.au/mecp2/">RettBASE</a>) lists <a href="http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic">4,225 different mutations</a>. Not all of them are in <em>MECP2</em>, but a large majority of them are.</span><br />
<br />
<span style="font-family: Trebuchet MS;">Mutations in <em>MECP2</em> can also be associated with conditions other than Rett syndrome: <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1734853/pdf/v038p00224.pdf">this article</a> describes mutations found in five children with Angelman syndrome. Two of them had deletions in exon 4, one had a two-nucleotide deletion in exon 3, and the others had single-base substitutions.</span><br />
<br />
<span style="font-family: Trebuchet MS;"><strong>How do these mutations affect protein function?</strong></span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">The MeCP2 protein has two regions (called domains) that are crucial to its function in the cell: the methyl-DNA binding domain (MBD), which allows it to bind to methylated cytosines, and the transcription repression domain (TRD), which binds to <a href="http://en.wikipedia.org/wiki/Histone_deacetylase">other enzymes</a> that condense chromosomal DNA and make it impossible for the enzymes reponsible for transcription to bind to it. MeCP2's role in transcription repression seems to be to bring the enzymes that do the actual repressing to its target sequences of DNA, rather than to block transcription itself.</span>
<img alt="" border="0" id="BLOGGER_PHOTO_ID_5630411650996474754" src="http://3.bp.blogspot.com/-CJrUKpKC4Zw/TiM9kLzdk4I/AAAAAAAAAzU/D_oReVM_UQc/s400/MeCP2%2BMBD%2Bstructure.png" style="cursor: hand; display: block; height: 300px; margin: 0px auto 10px; text-align: center; width: 350px;" /><span style="font-family: trebuchet ms; font-size: 85%;"><em>(Image of the structure of the MeCP2 methylDNA-binding domain, showing the amino acids affected by some of the more common mutations) </em></span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">The <em>MECP2</em> gene has four exons, of which three contain sequences encoding these domains: Exon 2 encodes most of the DNA-binding domain, with some of it spilling over into exon 3, and parts of exons 3 and 4 encode the transcription repressor domain. So, depending on where it occurs in the gene, a mutation might disrupt either the MeCP2 protein's DNA-binding capacity, or its ability to bind to those other, transcription-repressing enzymes. </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Most of the mutations associated with Rett syndrome (or other conditions mentioned in the above section) change the structure of one of those domains in such a way as to weaken, or completely destroy, its ability to bind to whatever it needs to bind to. <a href="http://www.jbc.org/content/276/5/3353.full">This article</a> describes the effect on DNA binding ability of several known mutations (including a few of the most common ones) that alter the amino-acid sequence of the MBD. The mutation with the greatest effect on MeCP2's DNA-binding ability, p.R111G, swaps out a positively-charged amino acid on the long, flexible loop within the MBD for a nonpolar one; since that loop normally lies close to the sugar-and-phosphate "backbone" of the DNA (the part of the DNA to which the A's, T's, G's and C's all attach, and which forms the two outer ridges of the double helix), and since that backbone carries a negative charge (from all the phosphate groups), knocking out positively-charged amino acids in this region will disrupt the attraction between the DNA and the methylDNA-binding region of MeCP2.</span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Another mutation that can cause a sharp decline in DNA-binding ability, which also happens to be one of the most commonly-occurring mutations in people with Rett syndrome, is p.R133C, which also replaces a positively-charged amino acid with a nonpolar one. This one occurs in a different part of the MBD than p.R111G does, a "beta sheet" made up of long, flat strings of amino acids laid side by side. One of the short loops connecting two of the component strands has a sequence of five amino acids with hydrophobic side chains that create a "pocket" sequestering the methyl groups attached to the DNA. It may not always lead to loss of function, though; <a href="http://www.sciencedirect.com/science/article/pii/S038776040100345X">this group of mostly Japanese researchers</a> conducted a similar analysis (full text <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735522/pdf/v040p00487.pdf">here</a>) of protein function, comparing some of the most common mutant versions of MeCP2 with its normal, "wild-type" form, and they found that the R133C variant bound to DNA almost as readily as the wild-type MeCP2 did. </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Other mutations associated with a near-total loss of DNA-binding ability are p.G114P, which replaces an amino acid in the middle of the long, flexible loop described above with one whose rigidly-structured, bulkier sidechain would greatly restrict the loop's ability to move and re-fold itself to fit into the groove of the DNA helix; p.D121A and p.D121E, which substitute amino acids with, respectively, nonpolar and negatively-charged sidechains for one with a positively-charged sidechain on one of the strands of the beta-sheet comprising another of the MBD's DNA-contacting surfaces; two other fairly common mutations, p.R106W and p.F155S, throw off the protein's overall folding to such an extent that it becomes unstable at body temperature. </span><br />
<span style="font-family: Trebuchet MS;"><br /></span>
<span style="font-family: Trebuchet MS;">Several mutations cause transcription of <em>MECP2</em> to stop prematurely, leading to the production of an incomplete protein. Depending on where the erroneous "stop" signal occurs, the resulting protein might be missing all or part of its transcription-repressor domain.</span><br />
<br />
<span style="font-family: Trebuchet MS;">Mutations occurring downstream of the transcription-repressor domain have also been associated with problems; <a href="http://nar.oxfordjournals.org/content/28/21/4172.full">this experiment</a> showed that mutant versions of MeCP2 that don't have the long tail following the TRD are less stable than wild-type MeCP2, and tend to break down quickly in the cellular environment. </span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>How common are they?</strong></span><br />
<br />
<span style="font-family: trebuchet ms;"><a href="http://www.nature.com/ejhg/journal/v13/n11/full/5201479a.html">This article in the <em>European Journal of Human Genetics</em></a> lists eight <em>MECP2</em> mutations its authors consider "common," along with each mutation's prevalence among the people with Rett syndrome listed in either the British Isles Rett Survey or the Australian Rett Syndrome Database. Of the 524 cases they looked at, 65 (12.8%) had the mutation p.T158M, which is the substitution of thymine for cytosine at nucleotide #473; 58 (11.1%) had the mutation p.R168X, which is the substitution of thymine for cytosine at nucleotide #502; 44 (8.4%) had the mutation p.R270X, which is the substitution of thymine for cytosine at nucleotide #808; and 42 (8%) had the mutation p.R255X, which is the substitution of thymine for cytosine at nucleotide #763. The other four mutations listed as "common" in this paper --- p.R106W (thymine substituted for cytosine at nucleotide 316), p.R133C (thymine for cytosine at nucleotide 397), p.R294X (thymine for cytosine at nucleotide 880) and p.R306C (thymine for cytosine at nucleotide 916) all account for between 3 and 7 percent of all cases surveyed.</span><br />
<br />
<span style="font-family: trebuchet ms;"><a href="http://www.neurology.org/content/56/11/1486.short">Another article</a> (full text <a href="http://biostat.mc.vanderbilt.edu/wiki/pub/Main/BonnieLaFleur/neurology_paper_IPG.pdf">here</a>) also found those eight mutations occurred several times in their sample of 116 people with Rett syndrome; these researchers also found p.T158M to be the most common, present in 12 different people. (The next-most common ones were p.R270X, found in eight people, and p.R255X and p.R106W, each found in seven people). This study also listed three other mutations in its table of "recurring" mutations: a substitution of guanine for cytosine at nucleotide 455 (observed four times), a substitution of thymine for cytosine at nucleotide 965 (observed twice), and a modification of a splice site in exon 4 (an AG sequence becomes GG; this permutation was also observed only twice).</span><br />
<br />
<span style="font-family: trebuchet ms;">RettBASE also <a href="http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=mut-freq">ranks the various mutations by frequency of occurrence</a>: there, too, p.T158M is the most common, with 363 known occurrences and accounting for 8.59% of all mutations identified so far. Most of the mutations (about two-thirds) listed there are unique. </span><br />
<span style="font-family: trebuchet ms;"><br /></span>
<span style="font-family: trebuchet ms;">Rett syndrome occurs in between 1:10,000 and 1:22,000 girls, and has only been recorded in 20 boys, ever. (Usually if a boy is born with the kind of mutations that would lead to Rett syndrome in a girl, he dies). So when I say a given mutation is found in, say, 10% of all people with Rett syndrome, that would translate into between 1:100,000 and 1:220,000 for its frequency among <em>all</em> people. So, while some <em>MECP2</em> mutations might be less rare than others, I'd say they're all rare.</span><br />
<span style="font-family: Trebuchet MS;"><strong><br /></strong></span>
<span style="font-family: Trebuchet MS;"><strong>Database entries for this gene:</strong> </span><br />
<br />
<span style="font-family: Trebuchet MS;"><a href="http://autism.mindspec.org/humangene/detail/MECP2">AutDB</a>, <a href="http://uswest.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000169057;r=X:153287024-153402578">Ensembl</a>, <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=full_report&list_uids=4204">Entrez Gene</a>, <a href="http://www.genecards.org/cgi-bin/carddisp.pl?gene=MECP2">GeneCards</a>, <a href="http://ghr.nlm.nih.gov/gene/MECP2">Genetics Home Reference</a>, <a href="http://www.wikigenes.org/e/gene/e/4204.html">WikiGenes</a></span><br />
<br />
<span style="font-family: Trebuchet MS;"><strong>Sources:</strong> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+genetics&rft_id=info%3Apmid%2F10508514&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Rett+syndrome+is+caused+by+mutations+in+X-linked+MECP2%2C+encoding+methyl-CpG-binding+protein+2.&rft.issn=1061-4036&rft.date=1999&rft.volume=23&rft.issue=2&rft.spage=185&rft.epage=188&rft.artnum=&rft.au=Amir+RE&rft.au=Van+den+Veyver+IB&rft.au=Wan+M&rft.au=Tran+CQ&rft.au=Francke+U&rft.au=Zoghbi+HY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CGenetics%2C+Neurology%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nature+genetics&rft_id=info%3Apmid%2F10508514&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Rett+syndrome+is+caused+by+mutations+in+X-linked+MECP2%2C+encoding+methyl-CpG-binding+protein+2.&rft.issn=1061-4036&rft.date=1999&rft.volume=23&rft.issue=2&rft.spage=185&rft.epage=188&rft.artnum=&rft.au=Amir+RE&rft.au=Van+den+Veyver+IB&rft.au=Wan+M&rft.au=Tran+CQ&rft.au=Francke+U&rft.au=Zoghbi+HY&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CGenetics%2C+Neurology%2C+Molecular+Biology">Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, & Zoghbi HY (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. <span style="font-style: italic;">Nature genetics, 23</span> (2), 185-188 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/10508514" rev="review">10508514</a></span> </span><br />
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<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Human+Molecular+Genetics&rft_id=info%3Adoi%2F10.1093%2Fhmg%2F9.9.1377&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=MECP2+mutations+account+for+most+cases+of+typical+forms+of+Rett+syndrome&rft.issn=14602083&rft.date=2000&rft.volume=9&rft.issue=9&rft.spage=1377&rft.epage=1384&rft.artnum=http%3A%2F%2Fwww.hmg.oupjournals.org%2Fcgi%2Fdoi%2F10.1093%2Fhmg%2F9.9.1377&rft.au=Bienvenu%2C+T.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CNeurology%2C+Molecular+Biology%2C+Genetics">Bienvenu, T. (2000). MECP2 mutations account for most cases of typical forms of Rett syndrome <span style="font-style: italic;">Human Molecular Genetics, 9</span> (9), 1377-1384 DOI: <a href="http://dx.doi.org/10.1093/hmg/9.9.1377" rev="review">10.1093/hmg/9.9.1377</a></span></span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Human+mutation&rft_id=info%3Apmid%2F11524737&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Five+novel+frameshift+mutations+in+exon+3+and+4+of+the+MECP2+gene+identified+in+Rett+patients%3A+Consequences+for+the+molecular+diagnosis+strategy.&rft.issn=1059-7794&rft.date=2001&rft.volume=18&rft.issue=3&rft.spage=251&rft.epage=252&rft.artnum=&rft.au=Bienvenu+T&rft.au=Souville+I&rft.au=Poirier+K&rft.au=Aquaviva+C&rft.au=Burglen+L&rft.au=Amiel+J&rft.au=H%C3%A9ron+B&rft.au=Kaminska+A&rft.au=Couvert+P&rft.au=Beldjord+C&rft.au=Chelly+J&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics"><br /></span></span>
<span style="font-family: Trebuchet MS;">
<span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Human+mutation&rft_id=info%3Apmid%2F11524737&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Five+novel+frameshift+mutations+in+exon+3+and+4+of+the+MECP2+gene+identified+in+Rett+patients%3A+Consequences+for+the+molecular+diagnosis+strategy.&rft.issn=1059-7794&rft.date=2001&rft.volume=18&rft.issue=3&rft.spage=251&rft.epage=252&rft.artnum=&rft.au=Bienvenu+T&rft.au=Souville+I&rft.au=Poirier+K&rft.au=Aquaviva+C&rft.au=Burglen+L&rft.au=Amiel+J&rft.au=H%C3%A9ron+B&rft.au=Kaminska+A&rft.au=Couvert+P&rft.au=Beldjord+C&rft.au=Chelly+J&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics">Bienvenu T, Souville I, Poirier K, Aquaviva C, Burglen L, Amiel J, Héron B, Kaminska A, Couvert P, Beldjord C, & Chelly J (2001). Five novel frameshift mutations in exon 3 and 4 of the MECP2 gene identified in Rett patients: Consequences for the molecular diagnosis strategy. <span style="font-style: italic;">Human mutation, 18</span> (3), 251-252 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/11524737" rev="review">11524737</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=European+Journal+of+Neuroscience&rft_id=info%3Adoi%2F10.1111%2Fj.1460-9568.2011.07658.x&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=In+sickness+and+in+health%3A+the+role+of+methyl-CpG+binding+protein+2+in+the+central+nervous+system&rft.issn=0953816X&rft.date=2011&rft.volume=33&rft.issue=9&rft.spage=1563&rft.epage=1574&rft.artnum=http%3A%2F%2Fdoi.wiley.com%2F10.1111%2Fj.1460-9568.2011.07658.x&rft.au=D%C3%ADaz+de+Le%C3%B3n-Guerrero%2C+S.&rft.au=Pedraza-Alva%2C+G.&rft.au=P%C3%A9rez-Mart%C3%ADnez%2C+L.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CNeurology%2C+Molecular+Biology%2C+Biochemistry%2C+Cell+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=European+Journal+of+Neuroscience&rft_id=info%3Adoi%2F10.1111%2Fj.1460-9568.2011.07658.x&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=In+sickness+and+in+health%3A+the+role+of+methyl-CpG+binding+protein+2+in+the+central+nervous+system&rft.issn=0953816X&rft.date=2011&rft.volume=33&rft.issue=9&rft.spage=1563&rft.epage=1574&rft.artnum=http%3A%2F%2Fdoi.wiley.com%2F10.1111%2Fj.1460-9568.2011.07658.x&rft.au=D%C3%ADaz+de+Le%C3%B3n-Guerrero%2C+S.&rft.au=Pedraza-Alva%2C+G.&rft.au=P%C3%A9rez-Mart%C3%ADnez%2C+L.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMedicine%2CNeurology%2C+Molecular+Biology%2C+Biochemistry%2C+Cell+Biology">Díaz de León-Guerrero, S., Pedraza-Alva, G., & Pérez-Martínez, L. (2011). In sickness and in health: the role of methyl-CpG binding protein 2 in the central nervous system <span style="font-style: italic;">European Journal of Neuroscience, 33</span> (9), 1563-1574 DOI: <a href="http://dx.doi.org/10.1111/j.1460-9568.2011.07658.x" rev="review">10.1111/j.1460-9568.2011.07658.x</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span atitle="A+case+of+a+Tunisian+Rett+patient+with+a+novel+double-mutation+of+the+MECP2+gene.&rft.issn=" au="Fendri-Kriaa+N&rft.au=" class="Z3988" date="2011&rft.volume=" epage="274&rft.artnum=" issue="2&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Apmid%2F21575601&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Biology%2CGenetics" title="ctx_ver="><br /></span></span>
<span style="font-family: Trebuchet MS;"><span atitle="A+case+of+a+Tunisian+Rett+patient+with+a+novel+double-mutation+of+the+MECP2+gene.&rft.issn=" au="Fendri-Kriaa+N&rft.au=" class="Z3988" date="2011&rft.volume=" epage="274&rft.artnum=" issue="2&rft.spage=" rfe_dat="bpr3.included=" rft_id="info%3Apmid%2F21575601&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" tags="Biology%2CGenetics" title="ctx_ver=">Fendri-Kriaa N, Hsairi I, Kifagi C, Ellouze E, Mkaouar-Rebai E, Triki C, Fakhfakh F, & The Tunisian network on mental retardation study (2011). A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene. <span style="font-style: italic;">Biochemical and biophysical research communications, 409</span> (2), 270-274 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21575601" rev="review">21575601</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Biological+Chemistry&rft_id=info%3Adoi%2F10.1074%2Fjbc.M007224200&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=DNA+Recognition+by+the+Methyl-CpG+Binding+Domain+of+MeCP2&rft.issn=00219258&rft.date=2000&rft.volume=276&rft.issue=5&rft.spage=3353&rft.epage=3360&rft.artnum=http%3A%2F%2Fwww.jbc.org%2Fcgi%2Fdoi%2F10.1074%2Fjbc.M007224200&rft.au=Free%2C+Andrew&rft.au=Robert+I.+D.+Wakefield&rft.au=Brian+O.+Smith&rft.au=David+T.+F.+Dryden&rft.au=Paul+N.+Barlow&rft.au=Adrian+P.+Bird&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Biological+Chemistry&rft_id=info%3Adoi%2F10.1074%2Fjbc.M007224200&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=DNA+Recognition+by+the+Methyl-CpG+Binding+Domain+of+MeCP2&rft.issn=00219258&rft.date=2000&rft.volume=276&rft.issue=5&rft.spage=3353&rft.epage=3360&rft.artnum=http%3A%2F%2Fwww.jbc.org%2Fcgi%2Fdoi%2F10.1074%2Fjbc.M007224200&rft.au=Free%2C+Andrew&rft.au=Robert+I.+D.+Wakefield&rft.au=Brian+O.+Smith&rft.au=David+T.+F.+Dryden&rft.au=Paul+N.+Barlow&rft.au=Adrian+P.+Bird&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology">Free, Andrew, Robert I. D. Wakefield, Brian O. Smith, David T. F. Dryden, Paul N. Barlow, & Adrian P. Bird (2000). DNA Recognition by the Methyl-CpG Binding Domain of MeCP2 <span style="font-style: italic;">Journal of Biological Chemistry, 276</span> (5), 3353-3360 DOI: <a href="http://dx.doi.org/10.1074/jbc.M007224200" rev="review">10.1074/jbc.M007224200</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Biochemistry+and+Cell+Biology&rft_id=info%3Adoi%2F10.1139%2Fo08-115&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Recent+advances+in+MeCP2+structure+and+function&rft.issn=0829-8211&rft.date=2009&rft.volume=87&rft.issue=1&rft.spage=219&rft.epage=227&rft.artnum=http%3A%2F%2Fwww.nrcresearchpress.com%2Fdoi%2Fabs%2F10.1139%2FO08-115&rft.au=Hite%2C+K.&rft.au=Adams%2C+V.&rft.au=Hansen%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMolecular+Biology%2C+Biochemistry"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Biochemistry+and+Cell+Biology&rft_id=info%3Adoi%2F10.1139%2Fo08-115&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Recent+advances+in+MeCP2+structure+and+function&rft.issn=0829-8211&rft.date=2009&rft.volume=87&rft.issue=1&rft.spage=219&rft.epage=227&rft.artnum=http%3A%2F%2Fwww.nrcresearchpress.com%2Fdoi%2Fabs%2F10.1139%2FO08-115&rft.au=Hite%2C+K.&rft.au=Adams%2C+V.&rft.au=Hansen%2C+J.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CMolecular+Biology%2C+Biochemistry">Hite, K., Adams, V., & Hansen, J. (2009). Recent advances in MeCP2 structure and function <span style="font-style: italic;">Biochemistry and Cell Biology, 87</span> (1), 219-227 DOI: <a href="http://dx.doi.org/10.1139/o08-115" rev="review">10.1139/o08-115</a></span> </span><br />
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<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Neurology&rft_id=info%3Apmid%2F11402105&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=MeCP2+mutations+in+children+with+and+without+the+phenotype+of+Rett+syndrome.&rft.issn=0028-3878&rft.date=2001&rft.volume=56&rft.issue=11&rft.spage=1486&rft.epage=1495&rft.artnum=&rft.au=Hoffbuhr+K&rft.au=Devaney+JM&rft.au=LaFleur+B&rft.au=Sirianni+N&rft.au=Scacheri+C&rft.au=Giron+J&rft.au=Schuette+J&rft.au=Innis+J&rft.au=Marino+M&rft.au=Philippart+M&rft.au=Narayanan+V&rft.au=Umansky+R&rft.au=Kronn+D&rft.au=Hoffman+EP&rft.au=Naidu+S&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CGenetics">Hoffbuhr K, Devaney JM, LaFleur B, Sirianni N, Scacheri C, Giron J, Schuette J, Innis J, Marino M, Philippart M, Narayanan V, Umansky R, Kronn D, Hoffman EP, & Naidu S (2001). MeCP2 mutations in children with and without the phenotype of Rett syndrome. <span style="font-style: italic;">Neurology, 56</span> (11), 1486-1495 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/11402105" rev="review">11402105</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Medical+Genetics&rft_id=info%3Adoi%2F10.1136%2Fjmg.40.7.487&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Heterogeneity+in+residual+function+of+MeCP2+carrying+missense+mutations+in+the+methyl+CpG+binding+domain&rft.issn=1468-6244&rft.date=2003&rft.volume=40&rft.issue=7&rft.spage=487&rft.epage=493&rft.artnum=http%3A%2F%2Fjmg.bmj.com%2Fcgi%2Fdoi%2F10.1136%2Fjmg.40.7.487&rft.au=Kudo%2C+S.&rft.au=Y.+Nomura&rft.au=M.+Segawa&rft.au=N.+Fujita&rft.au=M.+Nakao&rft.au=C.+Schanen&rft.au=M.+Tamura&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Medical+Genetics&rft_id=info%3Adoi%2F10.1136%2Fjmg.40.7.487&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Heterogeneity+in+residual+function+of+MeCP2+carrying+missense+mutations+in+the+methyl+CpG+binding+domain&rft.issn=1468-6244&rft.date=2003&rft.volume=40&rft.issue=7&rft.spage=487&rft.epage=493&rft.artnum=http%3A%2F%2Fjmg.bmj.com%2Fcgi%2Fdoi%2F10.1136%2Fjmg.40.7.487&rft.au=Kudo%2C+S.&rft.au=Y.+Nomura&rft.au=M.+Segawa&rft.au=N.+Fujita&rft.au=M.+Nakao&rft.au=C.+Schanen&rft.au=M.+Tamura&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology">Kudo, S., Y. Nomura, M. Segawa, N. Fujita, M. Nakao, C. Schanen, & M. Tamura (2003). Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain <span style="font-style: italic;">Journal of Medical Genetics, 40</span> (7), 487-493 DOI: <a href="http://dx.doi.org/10.1136/jmg.40.7.487" rev="review">10.1136/jmg.40.7.487</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Cell+Science&rft_id=info%3Adoi%2F10.1242%2Fjcs.016865&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Analysis+of+protein+domains+and+Rett+syndrome+mutations+indicate+that+multiple+regions+influence+chromatin-binding+dynamics+of+the+chromatin-associated+protein+MECP2+in+vivo&rft.issn=0021-9533&rft.date=2008&rft.volume=121&rft.issue=7&rft.spage=1128&rft.epage=1137&rft.artnum=http%3A%2F%2Fjcs.biologists.org%2Fcgi%2Fdoi%2F10.1242%2Fjcs.016865&rft.au=Kumar%2C+A.&rft.au=Kamboj%2C+S.&rft.au=Malone%2C+B.&rft.au=Kudo%2C+S.&rft.au=Twiss%2C+J.&rft.au=Czymmek%2C+K.&rft.au=LaSalle%2C+J.&rft.au=Schanen%2C+N.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Journal+of+Cell+Science&rft_id=info%3Adoi%2F10.1242%2Fjcs.016865&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Analysis+of+protein+domains+and+Rett+syndrome+mutations+indicate+that+multiple+regions+influence+chromatin-binding+dynamics+of+the+chromatin-associated+protein+MECP2+in+vivo&rft.issn=0021-9533&rft.date=2008&rft.volume=121&rft.issue=7&rft.spage=1128&rft.epage=1137&rft.artnum=http%3A%2F%2Fjcs.biologists.org%2Fcgi%2Fdoi%2F10.1242%2Fjcs.016865&rft.au=Kumar%2C+A.&rft.au=Kamboj%2C+S.&rft.au=Malone%2C+B.&rft.au=Kudo%2C+S.&rft.au=Twiss%2C+J.&rft.au=Czymmek%2C+K.&rft.au=LaSalle%2C+J.&rft.au=Schanen%2C+N.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology">Kumar, A., Kamboj, S., Malone, B., Kudo, S., Twiss, J., Czymmek, K., LaSalle, J., & Schanen, N. (2008). Analysis of protein domains and Rett syndrome mutations indicate that multiple regions influence chromatin-binding dynamics of the chromatin-associated protein MECP2 in vivo <span style="font-style: italic;">Journal of Cell Science, 121</span> (7), 1128-1137 DOI: <a href="http://dx.doi.org/10.1242/jcs.016865" rev="review">10.1242/jcs.016865</a></span>
</span><br />
<span style="font-family: Trebuchet MS;"><span atitle="A+novel+mutation+in+the+MECP2+gene+in+a+Korean+patient+with+Rett+syndrome.&rft.issn=" au="Lee+EY&rft.au=" class="Z3988" date="2011&rft.volume=" epage="96&rft.artnum=" included="1;bpr3.tags=" issue="1&rft.spage=" rft_id="info%3Apmid%2F21325263&rfr_id=" rft_val_fmt="info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=" title="ctx_ver=">Lee EY, Chung HJ, Ki CS, Yoo JH, & Choi JR (2011). A novel mutation in the MECP2 gene in a Korean patient with Rett syndrome. <span style="font-style: italic;">Annals of clinical and laboratory science, 41</span> (1), 93-96 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/21325263" rev="review">21325263</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+Zealand+medical+journal&rft_id=info%3Apmid%2F19652677&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Spectrum+of+MECP2+mutations+in+New+Zealand+Rett+syndrome+patients.&rft.issn=0028-8446&rft.date=2009&rft.volume=122&rft.issue=1296&rft.spage=21&rft.epage=28&rft.artnum=&rft.au=Raizis+AM&rft.au=Saleem+M&rft.au=MacKay+R&rft.au=George+PM&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CHealth%2CGenetics%2C+Epidemiology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=The+New+Zealand+medical+journal&rft_id=info%3Apmid%2F19652677&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Spectrum+of+MECP2+mutations+in+New+Zealand+Rett+syndrome+patients.&rft.issn=0028-8446&rft.date=2009&rft.volume=122&rft.issue=1296&rft.spage=21&rft.epage=28&rft.artnum=&rft.au=Raizis+AM&rft.au=Saleem+M&rft.au=MacKay+R&rft.au=George+PM&rfe_dat=bpr3.included=1;bpr3.tags=Medicine%2CHealth%2CGenetics%2C+Epidemiology">Raizis AM, Saleem M, MacKay R, & George PM (2009). Spectrum of MECP2 mutations in New Zealand Rett syndrome patients. <span style="font-style: italic;">The New Zealand medical journal, 122</span> (1296), 21-28 PMID: <a href="http://www.ncbi.nlm.nih.gov/pubmed/19652677" rev="review">19652677</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nucleic+Acids+Research&rft_id=info%3Adoi%2F10.1093%2Fnar%2Fgkn591&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=MECP2+genomic+structure+and+function%3A+insights+from+ENCODE&rft.issn=0305-1048&rft.date=2008&rft.volume=36&rft.issue=19&rft.spage=6035&rft.epage=6047&rft.artnum=http%3A%2F%2Fwww.nar.oxfordjournals.org%2Fcgi%2Fdoi%2F10.1093%2Fnar%2Fgkn591&rft.au=Singh%2C+J.&rft.au=Saxena%2C+A.&rft.au=Christodoulou%2C+J.&rft.au=Ravine%2C+D.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CGenetics+%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nucleic+Acids+Research&rft_id=info%3Adoi%2F10.1093%2Fnar%2Fgkn591&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=MECP2+genomic+structure+and+function%3A+insights+from+ENCODE&rft.issn=0305-1048&rft.date=2008&rft.volume=36&rft.issue=19&rft.spage=6035&rft.epage=6047&rft.artnum=http%3A%2F%2Fwww.nar.oxfordjournals.org%2Fcgi%2Fdoi%2F10.1093%2Fnar%2Fgkn591&rft.au=Singh%2C+J.&rft.au=Saxena%2C+A.&rft.au=Christodoulou%2C+J.&rft.au=Ravine%2C+D.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CGenetics+%2C+Molecular+Biology">Singh, J., Saxena, A., Christodoulou, J., & Ravine, D. (2008). MECP2 genomic structure and function: insights from ENCODE <span style="font-style: italic;">Nucleic Acids Research, 36</span> (19), 6035-6047 DOI: <a href="http://dx.doi.org/10.1093/nar/gkn591" rev="review">10.1093/nar/gkn591</a></span> </span><br />
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nucleic+Acids+Research&rft_id=info%3Adoi%2F10.1093%2Fnar%2F28.21.4172&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Functional+consequences+of+Rett+syndrome+mutations+on+human+MeCP2&rft.issn=13624962&rft.date=2000&rft.volume=28&rft.issue=21&rft.spage=4172&rft.epage=4179&rft.artnum=http%3A%2F%2Fwww.nar.oupjournals.org%2Fcgi%2Fdoi%2F10.1093%2Fnar%2F28.21.4172&rft.au=Yusufzai%2C+Timur+M.&rft.au=Wolffe%2C+Alan+P.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology"><br /></span></span>
<span style="font-family: Trebuchet MS;"><span class="Z3988" title="ctx_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.jtitle=Nucleic+Acids+Research&rft_id=info%3Adoi%2F10.1093%2Fnar%2F28.21.4172&rfr_id=info%3Asid%2Fresearchblogging.org&rft.atitle=Functional+consequences+of+Rett+syndrome+mutations+on+human+MeCP2&rft.issn=13624962&rft.date=2000&rft.volume=28&rft.issue=21&rft.spage=4172&rft.epage=4179&rft.artnum=http%3A%2F%2Fwww.nar.oupjournals.org%2Fcgi%2Fdoi%2F10.1093%2Fnar%2F28.21.4172&rft.au=Yusufzai%2C+Timur+M.&rft.au=Wolffe%2C+Alan+P.&rfe_dat=bpr3.included=1;bpr3.tags=Biology%2CBiochemistry%2C+Molecular+Biology">Yusufzai, Timur M., & Wolffe, Alan P. (2000). Functional consequences of Rett syndrome mutations on human MeCP2 <span style="font-style: italic;">Nucleic Acids Research, 28</span> (21), 4172-4179 DOI: <a href="http://dx.doi.org/10.1093/nar/28.21.4172" rev="review">10.1093/nar/28.21.4172</a></span></span>Lindsayhttp://www.blogger.com/profile/10860246538349067232noreply@blogger.com0