A new locus on 3p23-p25 for an autosomal-dominant limb-girdle muscular dystrophy, LGMD1H

Abstract

Limb-girdle muscular dystrophies (LGMDs) 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-generation Italian family with autosomal-dominant LGMD. A total of 11 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 of life, which fulfilled the consensus diagnostic criteria for LGMD. Earlier onset of the disease was observed 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 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 (theta=0) at marker D3S1286 and D3S3613, whereas non-parametric analysis reached a P-value=0.0004. Four candidate genes within the refined region were analysed but did not reveal any mutations. Our findings further expand the clinical and genetic heterogeneity of LGMDs.

Figure 1

Pedigree of the family affected by the previously unknown AD LGMD form and haplotype analysis of microsatellite markers from chromosome 3p23–p25. The haplotype segregating with the disease is ‘boxed'. Black filled symbols indicate affected subjects; clear symbols indicate the unaffected subjects.

Figure 2

Southern blot performed on DNA extracted from skeletal muscle biopsy samples.

Figure 3

Diagrammatic representation of the region 3p22–p25.3. (a) Schematic map of the short arm of the chromosome 3 showing markers and genes of interest located between 11 and 42 Mb. (b) Multipoint LOD scores between the disease and markers on chromosome 3p.