Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy

Am J Hum Genet. 2002 Jun;70(6):1446-58. doi: 10.1086/340608. Epub 2002 Apr 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Base Sequence
  • Child
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2 / genetics*
  • Collagen Type VI / deficiency
  • Collagen Type VI / genetics*
  • Consanguinity
  • Exons / genetics
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Introns / genetics
  • Lod Score
  • Male
  • Microsatellite Repeats / genetics
  • Muscular Dystrophies / congenital
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / physiopathology*
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single-Stranded Conformational
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Collagen Type VI
  • RNA, Messenger

Associated data

  • OMIM/MIM158810
  • OMIM/MIM254090