A new locus on 3p23-p25 for an autosomal dominant limb-girdle muscular dystrophy, LGMD1H
Résumé
The limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of neuromuscular disorders with a selective or predominant involvement of shoulder and pelvic-girdles. We clinically examined 19 members in a four generations Italian family with autosomal dominant LGMD. Eleven subjects were affected. Clinical findings showed variable expressivity in terms of age at onset and disease severity. Five subjects presented with a slowly progressive proximal muscle weakness, in both upper and lower limbs, with onset during the fourth-fifth decade that fulfilled the consensus diagnostic criteria for LGMD. Earlier onset of the disease was found in a group of patients presenting with muscle weakness and/or calf hypertrophy and/or occasionally high CK and lactate serum levels. Two muscle biopsies showed morphological findings compatible with MD associated with subsarcolemmal accumulation of mitochondria and the presence of multiple mitochondrial DNA deletions. A genome wide scan performed by using microsatellite markers mapped the disease on chromosome 3p23-p25.1 locus in a 25-cM region between markers D3S1263 and D3S3685. The highest two-point LOD score was 3.26 (θ=0) at marker D3S1286 and D3S3613, while non parametric analysis reached a p value =0.0004. Four candidate genes within the refined region were analyzed but did not reveal any mutations. Our findings further expand the clinical and genetic heterogeneity of LGMDs.
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