RETT syndrome

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MECP2 and its MUTATIONS

The MeCP2 gene was identified for the first time in mice in 1992 by the laboratory of A. Bird (Lewis et al., 1992). The human gene was identified in 1996 (D’Esposito et al., 1996). This work was performed long before we found out that mutations in this gene were causing a genetic disease.
The human gene spans 76 kilobases of genomic DNA between the interleukin receptor associated kinase (IRAK) gene and an eye color pigment gene (RCP). It is composed of 4 exons that are transcribed from the telomere to the centromere. The open reading frame has a size of 1461 nucleotides and encodes a 486 amino acids MeCP2 protein.. It is ubiquitously expressed (Reichwald et al., 2000) and it is subject to X-chromosome inactivation.

In early 2005, an alternative form of the MeCP2 protein was described. This transcript initiates traduction in exon 1 and does not contain exon 2. The resulting protein has a different size (498 amino acids instead of 486) and has a different N-terminus (21 amino acids) (Mnatzakanian et al., 2005).

In mice, the Mecp2 gene is expressed both in the embryo and in the adult. However, the expression level is low during the early phases of development (Meehan et al., 1992). In humans, three different transcripts are present (1.8, 7.5 and 10 kb) and they are generated by the use of three different polyadenylation signals in the 3’ non translated region. The functional significance of these three forms is currently not known, although regional differences have been demonstrated in an australian study (Pelka et al., 2005).

exon 1

exon 2

exon 3

exon 4

Mecp2-e1 isoform (498 amino acids protein)

Mecp2-e2 isoform (486 amino acids protein)

Mutations in the MECP2 gene are found in more than 95% of girls affected by typical Rett syndrome. All types of mutation are found in this gene :


- missense mutations (replacement of one amino acid by another amino acid inside the MECP2 protein), for example T158M (threonin at position 158 replaced by a methionin).


  1. -nonsense mutations (replacement of one amino acid by a signal of arrest of the synthesis of the MECP2 protein), for example R294X (arrest of protein synthesis after amino acid arginin (R) at position 294).


- deletions or insertions (from 1 nucleotide to several thousand).



If you are not familiar with these concepts or would like more information, follow this link.



In addition to the mutations associated with Rett syndrome,, we know that mutations in MECP2 are also causing a large number of other neurological disorders : variant forms of Rett syndrome (see the dedicated page of our site), non syndromic mental retardation, severe neonatal encephalopathy in males, autism spectrum disorders.

In all these cases a mutation in the MECP2 gene causes a neurological disorder. One of this disorders is Rett syndrome, which is probably the most frequent phenotype.




Most frequent mutations in french patients (Philippe et al. 2005) :

R168X (11.5%)

R270X (9%)

R255X (8.7%)

T158M (8.3%)

R306C (6.8%)

R294X (5.9%)

R133C (4.2%)

R106W (4.2%)


90.8% of all mutations are located in exon 4