Spectrum of MECP2 Mutations in Rett Syndrome

Abstract

Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. We have collected the results of MECP2 analysis conducted in four laboratories in France. A total of 301 RTT alleles have been analyzed, demonstrating a total of 69 different mutations so far observed and accounting for 64% of MECP2 genes in RTT patients living in France. R168X (11.5%) is the most common of MECP2 mutations, followed by R255X (10.9%), R270X (10.5%), T158M (7.8%), and R306C (6.8%). Only 10 mutations had a relative frequency > 2%. A total of 59 mutations were found in a small number of RTT alleles (from 1 to 2). These data demonstrate the high allelic heterogeneity of RTT in France and provide information relevant to the development of strategies for molecular diagnosis and genetic counseling in RTT families.

DNA Recognition by the Methyl-CpG Binding Domain of MeCP2

“…Amino acids Arg-106 and Phe-155 have side chains that both contribute to the hydrophobic core of the MBD domain (19) and are mutated to tryptophan and serine, respectively, in specific Rett syndrome cases. Further occurrences of the R106W mutation have since been identified (13,16,18), and R106Q and F155I mutations have also recently been found in Rett syndrome patients (14,18). The R106W protein was found to bind methylated DNA very poorly, whereas the F155S mutant, although forming a complex at fairly low protein concentrations, did not shift the probe to completion (Fig.…”

“…The mutation S134A was also seen to cause a moderate reduction in binding affinity. Ser-134 was found to be mutated to cysteine in cases of Rett syndrome (14,16), and the reduction in binding affinity caused by mutating this residue may thus contribute to the pathology.…”

“…This disorder is a childhood-onset regressive disease that causes loss of speech and hand movement, coupled with autistic behavior, microencephaly, and growth retardation and affects one in every 10,000 -15,000 live female births (11,12). Mutations found in the DNA of Rett syndrome patients include frameshift mutations generating truncations within the MBD, the transcription repression domain, or the C terminus of MeCP2, nonsense mutations preceding and immediately downstream of the MBD or within the transcription repression domain, or most interestingly, missense mutations within the MBD and transcription repression domain domains (10,(13)(14)(15)(16)(17)(18). It is of particular interest to determine what effects this latter class of mutations might have on the ability of the MeCP2 protein to carry out its functions of methylated DNA binding and transcriptional repression.…”

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers

“…Most studies have found an association between skewed X inactivation and a milder phenotype, 17,26,28,31 whereas one study also found an association between skewed X inactivation and a more severe phenotype. 28 Our results support the reported association between a milder phenotype and skewed X inactivation, as we found a higher mean degree of skewing in mild cases than in moderate or severe cases.…”

Methyl CpG binding proteins: coupling chromatin architecture to gene regulation

“…Stabilization generally occurs and most patients survive into adulthood (Rett, 1966;Hagberg et al, 1983;Hagberg, 1985). In the past year, several groups have reported similar ®ndings, expanding the number of MeCP2 mutations reported to in excess of 90 mutations in more than 400 individuals Buyse et al, 2000;Bienvenu et al, 2000;Cheadle et al, 2000;Hampson et al, 2000;Huppke et al, 2000;Kim and Cook, 2000;Obata et al, 2000;Wan et al, 1999;Xiang et al, 2000). Most groups report that more than 80% of classic Rett cases examined have mutations in the X-linked MeCP2 gene.…”