Résumé :
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Communication n° 607 Mutations in the coding sequence of the SEPN1 gene encoding the selenoprotein N (SelN) are responsible for Rigid Spine Muscular Dystrophy (RSMD1), multiminicore disease (MmD) and desmin-related myopathy with Mallory Body-like inclusions (MB-DRM). Here we report, in a patient presenting a mild RSMD phenotype, a homozygous mutation in the SECIS untranslated region of SEPN1. Genetic analyses were performed on genomic DNA extracted from leucocytes by amplifying and sequencing of the coding sequence and 3'UTR of SEPN1. Fibroblasts were cultured from a skin biopsy. Immunoblotting of total proteins was performed with polyclonal antibodies. Total RNAs were extracted from cultured fibroblasts and quantitative PCR was carried out with the LightCycler real-time PCR machine. The patient is a female of Syrian origin presenting with neck weakness since early childhood. After her second pregnancy, she developed a restrictive respiratory insufficiency. At age 44 she presented with an elongated neck and pelvic girdle weakness, a mild scapula alata and scoliosis. Contractures were noted in the cervical spine and in the Achilles tendons. We identified a homozygous nucleotide transition in the 3'untranslated SECIS domain (g. 17195 T>C). In cultured fibroblasts, mRNA levels were significantly reduced to 25% as compared to those from a control and Western blot analyses revealed a drastic reduction of SelN. This is the first mutation identified in the SECIS element, a stem-loop structure located in the 3' untranslated region allowing, through its interaction with trans-acting partners, the insertion of a selenocysteine residue at the UGA/Sec codon. This nucleotide change affects the so-called "non-Watson-Crick" quartet in the core of the SECIS hairpin and leads to a drastic reduction in both the SelN mRNA and protein levels. Our findings suggest that the mutation abolishes binding between SECIS and SECIS binding protein 2 (SBP2), thereby preventing co-translational incorporation of selenocysteine and SelN synthesis and leading to the RSMD phenotype.
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