Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36

Classical congenital muscular dystrophies (CMDs) are autosomal recessive neuromuscular disorders characterized by early onset of hypotonia and weakness, atrophy of limbs and trunk muscles, contractures, and dystrophic changes in the muscle biopsy. So far, only one gene, LAMA2 (6q2), which encodes the laminin alpha 2 chain (or merosin), has been identified in these disorders. Mutations in LAMA2 cause CMD with complete or partial :merosin deficiency, detectable by immunocytochemistry ion muscle biopsies, and account for similar to 50%, of CMD cases. In a large consanguineous family (11 siblings) comprising three children affected by CMD without merosin deficiency, we undertook a genomewide search by homozygosity mapping and analyzed 380 microsatellite markers. The affected children were homozygous for several markers on chromosome 1p35-36. We ident ified two additional consanguineous families with affected children who also showed linkage to this locus. A maximum cumulative LOD score of 4.48, at a recombination fraction of .00, was obtained with D1S2885. A consistent feature in these three families was the presence of early rigidity of the spine, scoliosis, and reduced vital capacity, as found in rigid-spine syndrome (RSS). This study is the first description of a locus for a merosin-positive CMD and will help to better define the nosology of RSS.