Mutation analysis of the MECP2 gene in patients of Slavic origin with Rett syndrome: novel mutations and polymorphisms

Abstract

Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder in females, is caused mainly by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). Here we report mutation analysis of the MECP2 gene in 87 patients with RTT from the Czech and Slovak Republics, and Ukraine. The patients, all girls, with classical RTT were investigated for mutations using bi-directional DNA sequencing and conformation sensitive gel electrophoresis analysis of the coding sequence and exon/intron boundaries of the MECP2 gene. Restriction fragment length polymorphism analysis was performed to confirm the mutations that cause the creation or abolition of the restriction site. Mutation-negative cases were subsequently examined by multiple ligation-dependent probe amplification (MLPA) to identify large deletions. Mutation screening revealed 31 different mutations in 68 patients and 12 non-pathogenic polymorphisms. Six mutations have not been previously published: two point mutations (323T>A, 904C>T), three deletions (189_190delGA, 816_832del17, 1069delAGC) and one deletion/inversion (1063_1236del174;1189_1231inv43). MLPA analysis revealed large deletions in two patients. The detection rate was 78.16%. Our results confirm the high frequency of MECP2 mutations in females with RTT and provide data concerning the mutation heterogeneity in the Slavic population.

Molecular screening of MECP2 gene in a cohort of Lebanese patients suspected with Rett syndrome: report on a mild case with a novel indel mutation

“…The parents were not tested to confirm the pathogenicity of the mutation. However, as the latter was found in a patient with typical features of RTT, and because single amino acid deletions were previously reported in RTT (Zahorakova et al 2007), we strongly suspect that E365del is pathogenic. Mutations between bp 1030 and 1207 of the MECP2 gene, a hotspot region for deletions at the 3′ end of the gene, are usually seen in mildly affected patients (Huppke et al 2002), which is different from our case.…”

“…The parents were not tested to confirm the pathogenicity of the mutation. However, as the latter was found in a patient with typical features of RTT, and because single amino acid deletions were previously reported in RTT (Zahorakova et al . 2007), we strongly suspect that E365del is pathogenic.…”

Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression

“…Besides the classical form, several variant forms such as mental retardation with spasticity, congenital hypotonia with infantile spasms or severe neonatal encephalopathy in males have been delineated. Although in about 90% of patients with classical Rett syndrome mutations or deletions of the X-linked MECP2 gene were detectable, less than 50% of atypical patients showed MECP2 defects [Fukuda et al, 2005;Kammoun et al, 2004;Li et al, 2007;Zahorakova et al, 2007]. Few of the MECP2 negative patients were recently shown to suffer from CDKL5 [Archer et al, 2006;Weaving et al, 2004] or FOXG1 [Ariani et al, 2008;Mencarelli et al, 2010;Philippe et al, 2010] mutations.…”

Rett Syndrome: North American Database

“…In this report, we describe the IRSA North American database and compare the findings with existing compilations. [7][8][9][10][11][12][13][14][15][16] Methods IRSA mailed a structured survey to 2994 members in the United States (2736) and Canada (158) requesting specific information including date of birth, diagnosis (typical Rett syndrome, variant or atypical Rett syndrome, not Rett syndrome, or unknown), mutation testing, and testing results, if performed. We had no responses from 1439, yielding 1555 (52%) completed surveys.…”