title: Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
abstract: Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the alpha3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A-->G transition in the splice-donor site of intron 29 (6930+5A-->G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient's COL6A3 transcripts showed the presence of various mRNA species-one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency.
authors: INSERM U 523, Groupe Hospitalier Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors: Ercan
authors: E
authors: Demir
authors: Patrizia
authors: P
authors: Sabatelli
authors: Valérie
authors: V
authors: Allamand
authors: Ana
authors: A
authors: Ferreiro
authors: Behzad
authors: B
authors: Moghadaszadeh
authors: Mohamed
authors: M
authors: Makrelouf
authors: Haluk
authors: H
authors: Topaloglu
authors: Bernard
authors: B
authors: Echenne
authors: Luciano
authors: L
authors: Merlini
authors: Pascale
authors: P
authors: Guicheney
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D024142:Collagen Type VI / Q000172:deficiency / Q000235:genetics*; D003241:Consanguinity; D005091:Exons / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007438:Introns / Q000235:genetics; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009136:Muscular Dystrophies / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D024142:Collagen Type VI; D012333:RNA, Messenger