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dc.contributor.authorTorabi Farsani, Golara-
dc.descriptionPhD Thesisen_US
dc.description.abstractSince discovery of COL6A1, A2 and A3 as disease-causing genes in collagen VI-related myopathies, several investigations have been done to identify novel genes which are responsible for collagen VI-related myopathy phenotypes with no mutations in COL6A1-A3 genes. By exome sequencing of five affected individuals from pedigrees lying in the phenotypic spectrum of Bethlem-like myopathy but no mutations in COL6A1-A3 genes, we identified two missense and one splice variant mutation acting as dominant negative in the gene COL12A1 in three pedigrees with overall six affected individuals. In silico analysis predicted pathogenecity of these mutations. Immunohistochemical studies revealed in two missense mutations misfolded collagen XII could secrete to extracellular matrix but could not assemble to its structure, while for the splice variant mutation the misfolded protein could not secrete out of the cells. Phenotypic spectrum of collagen XII affected individuals from our cohort included mild to moderate progressive muscle weakness, joint hyperlaxity, skin involvements such as keloid formation and scoliosis. Studying suprastructure of extracellular matrix via electron microscopy in the affected individuals by in vitro collagen fibrillogenesis of concentrated collagen extracted from cell culture and collagen fibrils surrounded cultured fibroblast, we could not reveal any differences in fibril diameter. Adult fibroblast/ C2C12 coculture demonstrated extracellular matrix of affected individuals did not have properties which are required for increasing myoblast differentiation as it was seen in intact extracellular matrix. Our investigation on Bethlem-like myopathy heterogeneity introduced COL12A1 as the new disease-causing gene in Bethlem-like phenotype with no mutations in COL6A1-A3 genes. However, more research in this field is required to decipher pathogenic mechanism of collagen XII mutation.en_US
dc.publisherNewcastle Universityen_US
dc.titleGenetic heterogeneity in collagen VI-related myopathyen_US
Appears in Collections:Institute of Genetic Medicine

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