title: Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI α2(VI) chain.
abstract: Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem myopathy is relatively mild, and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem myopathy is rare, and our understanding of the molecular pathology is limited. We studied a patient with Bethlem myopathy. Electron microscopy of his muscle biopsy revealed abnormal mitochondria. We identified a homozygous COL6A2 p.D871N amino acid substitution in the C-terminal C2 A-domain. Mutant α2(VI) chains are unable to associate with α1(VI) and α3(VI) and are degraded by the proteasomal pathway. Some collagen VI is assembled, albeit more slowly than normal, and is secreted. These molecules contain the minor α2(VI) C2a splice form that has an alternative C terminus that does include the mutation. Collagen VI tetramers containing the α2(VI) C2a chain do not assemble efficiently into microfibrils and there is a severe collagen VI deficiency in the extracellular matrix. We expressed wild-type and mutant α2(VI) C2 domains in mammalian cells and showed that while wild-type C2 domains are efficiently secreted, the mutant p.D871N domain is retained in the cell. These studies shed new light on the protein domains important for intracellular and extracellular collagen VI assembly and emphasize the importance of molecular investigations for families with collagen VI disorders to ensure accurate diagnosis and genetic counseling.
authors.affiliation: From the Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville 3052, Australia.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Zamurs
authors.affiliation: Departments of Pathology and.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Idoate
authors.affiliation: Electron Microscopy Unit, Bio21 Molecular Science and Biotechnology Institute and.
authors.forename: Eric
authors.initials: E
authors.lastname: Hanssen
authors.affiliation: Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, 31008 Pamplona, Spain.
authors.forename: Asier
authors.initials: A
authors.lastname: Gomez-Ibañez
authors.affiliation: Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, 31008 Pamplona, Spain, Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, 31008 Pamplona, Spain, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28220 Madrid, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Pastor
authors.affiliation: From the Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville 3052, Australia, Department of Paediatrics, University of Melbourne, Parkville 3010, Australia, shireen.lamande@mcri.edu.au.
authors.forename: Shireen R
authors.initials: SR
authors.lastname: Lamandé
mesh_terms: D019943:Amino Acid Substitution; D015153:Blotting, Western; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003286:Contracture / Q000235:genetics* / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024142:Collagen Type VI; D012333:RNA, Messenger
keywords: Autosomal Recessive; Bethlem Myopathy; Collagen; Collagen VI; Extracellular Matrix Protein; Genetic Disease; Mitochondria; Muscular Dystrophy; Mutation