Abstract for presentation at 11th International Congress of Human Genetics

Collagen VI mutations in Ullrich congenital muscular dystrophy

  • Ms Rishika Pace, Murdoch Childrens Research Institute and The University of Melbourne, Australia
  • Dr Naomi Baker, Murdoch Childrens Research Institute, Australia
  • Ms Naomi Adams, Murdoch Childrens Research Institute, Australia
  • Ms Rachel Peat, The Children's Hospital at Westmead and University of Sydney, Australia
  • Prof Kathryn North, The Children's Hospital at Westmead and University of Sydney, Australia
  • Dr Shireen Lamande, Murdoch Childrens Research Institute and The University of Melbourne, Australia

    • Collagen VI mutations cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). BM is a relatively mild disease characterised by neonatal or early childhood onset of proximal muscle weakness and contractures of the fingers, elbows and ankles. In contrast, UCMD is severe and progressive. Affected individuals have generalised muscle weakness and wasting, proximal joint contractures, and marked distal hyperlaxity. These two muscular dystrophies have long been thought to be separate disorders with distinct modes of inheritance, BM being dominant and UCMD recessive. However, both dominant and recessive mutations have been identified in UCMD and it is becoming clear that there is a gradient of clinical severity in the collagen VI muscular dystrophies. Our work focuses on defining collagen VI mutations in muscular dystrophy patients and, importantly, on understanding their effects on the intracellular assembly of collagen VI monomers, dimers and tetramers, and the formation and structure of extracellular microfibrils. We are studying 28 UCMD patients. Sixteen patients have dominant mutations, 4 have recessive mutations and 3 do not have collagen VI mutations, suggesting that mutations in other genes can also cause this phenotype. Sequencing of the 3 collagen VI genes is ongoing in 5 patients. Surprisingly, 5 of the dominant mutations are glycine substitutions within the triple helix and are similar to mutations identified in BM patients. Ten patients have mutations that lead to in-frame deletions. Deletions towards the N-terminal end of the triple helix interfere with tetramer and microfibril assembly and result in a severe reduction of collagen VI in the matrix. These studies are providing new insights into the molecular pathology of collagen VI disorders allowing us to understand why apparently similar mutations produce very different clinical outcomes and why patients with similar phenotypes can have either recessive or dominant mutations.

    Conference Organiser - ICMS Pty Ltd