Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance

Abstract

Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two related conditions of differing severity. BM is a relatively mild dominantly inherited disorder characterized by proximal weakness and distal joint contractures. UCMD was originally regarded as an exclusively autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. We and others have subsequently modified this model when we described UCMD patients with heterozygous in-frame deletions acting in a dominant-negative way. Here we report 10 unrelated patients with a UCMD clinical phenotype and de novo dominant negative heterozygous splice mutations in COL6A1, COL6A2, and COL6A3 and contrast our findings with four UCMD patients with recessively acting splice mutations and two BM patients with heterozygous splice mutations. We find that the location of the skipped exon relative to the molecular structure of the collagen chain strongly correlates with the clinical phenotype. Analysis by immunohistochemical staining of muscle biopsies and dermal fibroblast cultures, as well as immunoprecipitation to study protein biosynthesis and assembly, suggests different mechanisms each for exon skipping mutations underlying dominant UCMD, dominant BM, and recessive UCMD. We provide further evidence that de novo dominant mutations in severe UCMD occur relatively frequently in all three collagen VI chains and offer biochemical insight into genotype-phenotype correlations within the collagen VI-related disorders by showing that severity of the phenotype depends on the ability of mutant chains to be incorporated in the multimeric structure of collagen VI.

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“…Type VI collagen has mostly been recognised through mutations in the genes COL6A1, COL6A2 and COL6A3 that encode its three constituent chains. These mutations cause muscle disorders, such as Bethlem myopathy, Ullrich congenital muscular dystrophy, limb-girdle muscular dystrophy and autosomal recessive myosclerosis [43][44][45][46]. This provides an interesting link to metabolic dysfunction, since type VI collagen mutations are associated with muscle abnormalities and muscle represents an important regulator of insulin resistance.…”

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“…dominant and recessive Ullrich CMD as well as dominant Bethlem myopathy, they discussed the different mechanisms by which the location of the skipped exon in relation to the molecular structure of the collagen chain and to the degree of interference on the collagen VI microfibrils assembly, strongly correlated with the clinical phenotype. Therefore, they add new evidence to the knowledge that in last instance the clinical severity depends on the ability of mutant chains to be incorporated in the final multimeric structure of collagen VI microfibrillar network 122 .…”

“…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] .…”

“…since the triple helical deletions are readily detectable by rT-PCr analysis, lampe et al 122 recommend that mutation analysis checks these regions first by rT-PCr prior to screen all the 107 coding exons.…”

“…As in normal conditions collagen VI is particularly abundant close to the cells and in intimate contact with basement membranes surrounding myocytes, its lack caused by heterozygous mutations in Col6 genes diminish the anchorage of collagen VI microfibrils to the extracellular matrix. Finally, lampe et al 122 recently concluded that in collagen VI related disorders the genotype-phenotype correlation does exist and that the type and location of exon skipping mutation is predictive for severity and inheritance. They compared the molecular data of patients with Ullrich CMD with de novo dominant negative heterozygous splice mutations in Col6A1, Col6A2, and Col6A3, Ullrich CMD with recessively acting splice mutations, and Bethlem myopathy with heterozygous splice mutations.…”