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Segregation between a frameshift SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy
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International audience. Facio-Scapulo-Humeral muscular Dystrophy (FSHD) is linked to a copy number reduction (n<10) of the 4q D4Z4 subtelomeric macrosatellite, in association with a DUX4-permissive haplotype. This main form of the disease is indicated as FSHD1. FSHD‐like phenotypes may also appear, in 5% of cases, in the absence of D4Z4 copy number reduction (FSHD2). In 70‐80% of these FSHD2 patients, variants of the SMCHD1 gene have been reported to segregate with DUX4 -compatible haplotypes and associate with D4Z4 hypomethylation. Here, we describe a family presenting neuromuscular symptoms reminiscent of FSHD but without D4Z4 copy number reduction. Bisulfite sequencing showed significant hypomethylation in a proximal region within D4Z4 in symptomatic cases of the family. Exome sequencing revealed a heterozygous insertion of 7 bp in exon 37 of the SMCHD1 gene (c.4614_4615 insTATAATA) segregating with clinical signs and producing a frameshift in the protein with a premature stop codon 4 amino acids after the insertion (p.A1539Yfs*4),potentially leading to a truncated protein with a putative dominant negative effect. At the transcript level both wild‐type and mutated alleles were detected although the mutated allele was weakly expressed in all patients’ tissues analyzed. In western blot full length protein was expressed at the same level than controls and truncated protein was not detected, excluding aploinsufficiency as pathological mechanism. Ongoing analysis of nonsense mediated degradation of the mutated transcript and quantification of relative allele expression will allow elucidating the cause of truncated protein bsence. By this work, we aim to sheds light on SMCHD1 mutated protein complex contribution to FSHD pathogenesis.
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