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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). Rett patients present an apparently normal psychomotor development during the first 6 to 18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. In the present study, we performed a mutational analysis of the MECP2 gene in 2 typical Rett syndrome patients and in 1 atypical Rett syndrome girl. The results showed the presence of 3 de novo point mutations in the C-terminal region: 2 novel mutations: c.1065C>A (p.S355R) and c.1030C>G (p.R344G) in the 2 typical Rett syndrome girls, but also the c.996C>T (p.S332S) mutation first described in the atypical Rett syndrome patient. [ABSTRACT FROM PUBLISHER]

LGMD (limb-girdle muscular dystrophy) and CMD (congenital muscular dystrophy) are two common forms of neuromuscular disorders which are distinguishable by their age of onset but with probably a similar underlying pathway. In the present study, we report immunohistochemical, Western-blot and genetic analyses in a large consanguineous Tunisian family with two branches, including seven patients sharing similar LGMD2 phenotype in one branch and one CMD patient in the other branch. Linkage analyses were compatible with the LGMD2A locus in one branch and the MDC1A (muscular dystrophy congenital type 1A) locus in the other branch. This result was supported by deficiency in merosin and calpain3 in the CMD patient and LGMD patients respectively. Mutation analysis revealed two distinct mutations: a c.8005delT frameshift deletion in exon 56 of the LAMA2 (laminin-α2) gene (MDC1A) was found in the CMD patient and a new homozygous mutation c.1536+1G>T in the donor splice site of intron 12 of the CAPN3 (calpain3) gene (LGMD2A) was found in the LGMD patients. RT-PCR (reverse transcription-PCR) performed on total RNA from a LGMD2A patient's muscle biopsy showed complete retention of intron 12 in CAPN3 cDNA, generating a PTC (premature termination codon) that potentially elicits degradation of the nonsense mRNA by NMD (nonsensemediated mRNA decay). Our results indicate that mRNA analysis is necessary to clarify the primary effect of genomic mutations on splicing efficiency that alters mRNA processing and expression level. [ABSTRACT FROM AUTHOR]

Rett syndrome is a severe disorder characterized by loss of acquired skills after a period of normal development in infant girls. It is caused mainly by mutations in the MECP2 gene. In this study, we reported mutations in the MECP2 gene in 7 Tunisian patients with classic Rett syndrome. The results showed the presence of a double mutation in 1 patient: p.R306C and c.1461+ 98insA, which create a new hypothetical polyadenylation site in the 3'UTR of the MECP2 gene. We also detected in another patient a new variant c.1461+ 92C>G in the 30UTR located previous to 34 bp from the polyadenylation site with a score of 4.085. This variation is located in a hypothetical splicing enhancer with a score of 1.96277 according to the ESE finder program. In the remaining 5 patients, we found 2 common mutations: p.T158M in 4 individuals and p.R168X in only 1 girl. [ABSTRACT FROM AUTHOR]