Clin Genet. 2006 Apr;69(4):319-26.
Clinical profiles of four patients with Rett syndrome carrying a novel exon 1 mutation or genomic rearrangement in the MECP2 gene
Bartholdi D, Klein A, Weissert M, Koenig N, Baumer A, Boltshauser E, Schinzel A, Berger W, Matyas G.
Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene encoding methyl CpG binding protein 2 (MeCP2). Recently, a new isoform of MeCP2 including exon 1 was identified. This new isoform is more abundantly expressed in brain than the isoform including exons 2-4. Very little is known about the phenotypes associated with mutations in exon 1 of MECP2 since only a limited number of RTT patients carrying such mutations have been identified so far. In this study, we screened a cohort of 20 girls with RTT for exon 1 mutations by sequencing and multiplex ligation-dependent probe amplification (MLPA). We identified one girl with a novel exon 1 mutation (c.30delCinsGA) by sequencing and three with genomic rearrangements by MLPA. Comparison of the phenotypes showed that the girls carrying a mutation or rearrangement encompassing exon 1 were more severely affected than the girls with rearrangements not affecting exon 1.Lay Summary
Mutations in the gene for MeCP2 are identified by directly reading the DNA sequence of the MeCP2 gene in the patient samples, and looking for DNA sequences different from the norm. Using this method, mutations in the MeCP2 gene have been found in ~80% of girls with classic Rett syndrome. However, very little is known about the patients whose mutations are exclusively found in a region of the recently discovered longer form of MeCP2, sometimes called MeCP2_e1. That is, are these patients more or less severely affected when their mutation is present in this region, known as "exon 1"? This is due to the fact that only a few patients with mutations in this newly found MeCP2 DNA region have been found. In fact, only 7 patients - 6 previous ones, and one discovered here - have mutations in exon 1. Thus, although the authors found more severe symptoms in girls with so-called "exon 1 mutations", they concede that patient numbers too low to make any final conclusions.