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.

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

“…Mutations in the genes that codify the three collagen VI subunits lead to the second most common form of CMD, Ullrich atonic-sclerotic CMD [72][73][74][75] and to Bethlem myopathy 76,77 that now is included into CMD classification 8 .…”

“…The concept of a spectrum of collagen VI-related disorders with marked clinical and genetic heterogeneity has emerged from the recent advances on the molecular mechanism of both diseases 69 . The complex genotype/phenotype correlations that have been broadly analysed in these two conditions clearly indicate that in both collagen VI-related disorders the main pathomechanism is due to the disruption of collagen VI anchorage to the basal lamina of the muscular fibers 74,75,[120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138] .…”

“…In relation to Ullrich phenotype, the initial molecular studies in Col6A2 and Col6A3 genes pointed only to recessive mutations 73,74,118 . lampe and Bushby 69 revised the literature about the type of mutations in Ullrich CMD and reported a large number of the mutations that introduce premature termination codons with consequent nonsense mediated mrNA decay and loss of the mutated chain; another common type of mutation is by splicing that leads to in-frame exonic deletions as well as in-frame genomic deletions.…”

Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC International Workshop, 23–24 November 2001, Naarden, The Netherlands

“…The two other mutations, a nonsense in the N-terminal domain in an Italian case (L. Merlini) and a splice site mutation inducing an in-frame deletion in the Moroccan family, were associated with much milder phenotypes. In both cases, the synthesis of abnormal alpha3 chains occurs, which is still able to bind alpha1 and alpha2 chains, and gets secreted in the extracellular compartment [17].…”

Therapy of Collagen VI-Related Myopathies (Bethlem and Ullrich)

“…Patients with de novo heterozygous mutations may have a severe phenotype, 9,10 whereas patients with recessive mutations may present a milder Bethlem-type disease. 11 In addition, in some patients with the UCMD phenotype, the role of collagen VI molecules has been excluded, suggesting genetic heterogeneity even for this condition. 9 -13 Prevalence has been estimated as 0.5:100,000 for BM and 0.1:100,000 for UCMD, 14 but these disorders are probably underdiagnosed.…”