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Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity
Author(s) -
Pace Rishika A.,
Peat Rachel A.,
Baker Naomi L.,
Zamurs Laura,
Mörgelin Matthias,
Irving Melita,
Adams Naomi E.,
Bateman John F.,
Mowat David,
Smith Nicholas J. C.,
Lamont Phillipa J.,
Moore Steven A.,
Mathews Katherine D.,
North Kathryn N.,
Lamandé Shireen R.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21439
Subject(s) - collagen vi , extracellular matrix , glycine , phenotype , fibroblast , microfibril , congenital muscular dystrophy , mutation , chemistry , pathology , biology , genetics , biochemistry , medicine , gene , amino acid , in vitro , cellulose
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. Ann Neurol 2008