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- Baker, N L, et al.
(författare)
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Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy
- 2005
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:2, s. 279-293
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). UCMD, a severe disorder characterized by congenital muscle weakness, proximal joint contractures and marked distal joint hyperextensibility, has been considered a recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In contrast, the milder disorder Bethlem myopathy shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2 and COL6A3. This model, where dominant mutations cause mild Bethlem myopathy and recessive mutations cause severe UCMD was recently challenged when a patient with UCMD was shown to have a heterozygous in-frame deletion in COL6A1. We have studied five patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain, one in the alpha1(VI) chain, one in alpha2(VI) and one in alpha3(VI). Collagen VI protein biosynthesis and assembly studies showed that these mutations act in a dominant negative fashion and result in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of alpha2(VI), which prevented collagen VI assembly. No collagen VI mutations were found in the fifth patient. These data demonstrate that rather than being a rare cause of UCMD, dominant mutations are common in UCMD, now accounting for four of the 14 published cases. Mutation detection in this disorder remains critical for accurate genetic counseling of patients and their families.
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| 2. |
- Baker, Naomi L., et al.
(författare)
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Molecular consequences of dominant Bethlem myopathy collagen VI mutations
- 2007
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 62:4, s. 390-405
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Dominant mutations in the three collagen VI genes cause Bethlem myopathy, a disorder characterized by proximal muscle weakness and commonly contractures of the fingers, wrists, and ankles. Although more than 20 different dominant mutations have been identified in Bethlem myopathy patients, the biosynthetic consequences of only a subset of these have been studied, and in many cases, the pathogenic mechanisms remain unknown. Methods: We have screened fourteen Bethlem myopathy patients for collagen VI mutations and performed detailed analyses of collagen VI biosynthesis and intracellular and extracellular assembly. Results: Collagen VI abnormalities were identified in eight patients. One patient produced around half the normal amount of alpha 1(VI) messenger RNA and reduced amounts of collagen VI protein. Two patients had a previously reported mutation causing skipping of COL6A1 exon 14, and three patients had novel mutations leading to in-frame deletions toward the N-terminal end of the triple-helical domain. These mutations have different and complex effects on collagen VI intracellular and extracellular assembly. Two patients had single amino acid substitutions in the A-domains of COL6A2 and COL6A3. Collagen VI intracellular and extracellular assembly was normal in one of these patients. Interpretation: The key to dissecting the pathogenic mechanisms of collagen VI mutations lies in detailed analysis of collagen VI biosynthesis and assembly. The majority of mutations result in secretion and deposition of structurally abnormal collagen VI. However, one A-domain mutation had no detectable effect on assembly, suggesting that it acts by compromising collagen VI interactions in the extracellular matrix of muscle.
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| 3. |
- Pace, Rishika A., et al.
(författare)
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Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity
- 2008
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 64:3, s. 294-303
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes. Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway. Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. Interpretation: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.
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