(Cross-posted from my other blog)
Where is it?
Near the very end of the X chromosome, at Xq28.
Here is a picture of its position relative to some other genes at that part of the X chromosome:
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 MECP2 appearing at the far left? That's the very end of a 24-page image. So, based on that I feel comfortable calling MECP2 one of the last genes on the X chromosome.
What does it do?
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. (More recent research has also found that it can also serve as a transcriptional activator). It has a lot of target genes, 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.
What mutant versions of this gene have been discovered?
(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)
This 1999 article in Nature Genetics (full text here) describes a genetic analysis of 29 girls with Rett syndrome* (8 of whom had a family history of the condition), which found seven point mutations (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 protein synthesis depends on grouping the nucleotides into threes, and stringing together the amino acids corresponding to each sequence of three nucleotides, or "codons". 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 "frameshift" mutations are much more likely than point mutations to result in a nonfunctional protein).
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.
Another genetic analysis described in a 2000 article in Human Molecular Genetics 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.
A 2004 analysis 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.
An article from this year describes a 41-base deletion in a Korean girl with Rett syndrome; the deleted region started at nucleotide #1152, in exon 4.
Another article from this year found a substitution of thymine for cytosine at nucleotide #535 in a Tunisian girl with Rett syndrome.
This article (full text here) 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.
This 2009 genomic analysis 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.
There are a lot more --- the International Rett Syndrome Foundation's database of mutations associated with Rett syndrome (RettBASE) lists 4,225 different mutations. Not all of them are in MECP2, but a large majority of them are.
Mutations in MECP2 can also be associated with conditions other than Rett syndrome: this article 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.
How do these mutations affect protein function?
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 other enzymes 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.
(Image of the structure of the MeCP2 methylDNA-binding domain, showing the amino acids affected by some of the more common mutations)
The MECP2 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.
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. This article 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.
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; this group of mostly Japanese researchers conducted a similar analysis (full text here) 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.
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.
Several mutations cause transcription of MECP2 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.
Mutations occurring downstream of the transcription-repressor domain have also been associated with problems; this experiment 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.
How common are they?
This article in the European Journal of Human Genetics lists eight MECP2 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.
Another article (full text here) 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).
RettBASE also ranks the various mutations by frequency of occurrence: 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.
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 all people. So, while some MECP2 mutations might be less rare than others, I'd say they're all rare.
Database entries for this gene:
AutDB, Ensembl, Entrez Gene, GeneCards, Genetics Home Reference, WikiGenes
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. Nature genetics, 23 (2), 185-188 PMID: 10508514
Bienvenu, T. (2000). MECP2 mutations account for most cases of typical forms of Rett syndrome Human Molecular Genetics, 9 (9), 1377-1384 DOI: 10.1093/hmg/9.9.1377
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. Human mutation, 18 (3), 251-252 PMID: 11524737
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 European Journal of Neuroscience, 33 (9), 1563-1574 DOI: 10.1111/j.1460-9568.2011.07658.x
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. Biochemical and biophysical research communications, 409 (2), 270-274 PMID: 21575601
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 Journal of Biological Chemistry, 276 (5), 3353-3360 DOI: 10.1074/jbc.M007224200
Hite, K., Adams, V., & Hansen, J. (2009). Recent advances in MeCP2 structure and function Biochemistry and Cell Biology, 87 (1), 219-227 DOI: 10.1139/o08-115
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. Neurology, 56 (11), 1486-1495 PMID: 11402105
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 Journal of Medical Genetics, 40 (7), 487-493 DOI: 10.1136/jmg.40.7.487
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 Journal of Cell Science, 121 (7), 1128-1137 DOI: 10.1242/jcs.016865
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. Annals of clinical and laboratory science, 41 (1), 93-96 PMID: 21325263
Raizis AM, Saleem M, MacKay R, & George PM (2009). Spectrum of MECP2 mutations in New Zealand Rett syndrome patients. The New Zealand medical journal, 122 (1296), 21-28 PMID: 19652677
Singh, J., Saxena, A., Christodoulou, J., & Ravine, D. (2008). MECP2 genomic structure and function: insights from ENCODE Nucleic Acids Research, 36 (19), 6035-6047 DOI: 10.1093/nar/gkn591
Yusufzai, Timur M., & Wolffe, Alan P. (2000). Functional consequences of Rett syndrome mutations on human MeCP2 Nucleic Acids Research, 28 (21), 4172-4179 DOI: 10.1093/nar/28.21.4172