O06 The satellite cell in male and female, developing and adult mice: evidence for functionally distinct stem cell populations

muscle weakness. In the world literature the genetic defect for this condition has been identified in two families, having the R279W mutation in the sarcomeric protein TTN, although cases without this mutation have already been reported. Methods: Two large pedigrees and an apparently sporadic case with CBM were included in this study. Clinical characteristics and diagnostic investigations of all affected family members was collected from charts and summarised. Western blot of C-terminal TTN protein was performed. Genome-wide 1000 microsatellite analysis was performed in one of the families to identify a linkage region and shared haplotype. Exome sequencing was performed on 4 patients. Results: Onset of disease was usually in middle-age, with tibialis anterior being the earliest and most severely affected muscle. Pulmonary function tests indicated low FEV1 and FVC, with worsening when supine. Cardiac involvement was not present. Muscle pathology was nonspecific in some affected patients. Electromyography demonstrated necrotising myopathic process in the majority of patients. MRI invariably revealed signal abnormalities of semitendinosus muscle. Blot of C-terminal TTN protein was normal. A single 20 cM linkage region on chromosome 2 was identified. Exome sequencing detected the disease mutation and identified other candidates for exclusion with segregation analysis. Conclusions: We report the disease gene for these patients with CBM, and describe in detail the phenotype and diagnostic investigations from these three pedigrees. Genetic testing for these CBM genes should be performed in patients with myopathy and early respiratory failure if muscle pathology reveals cytoplasmic bodies or is nonspecific. Acknowledgements: GP is the recipient of funding from the Clinician Investigator Program from the University of British Columbia in Vancouver, Canada, and a Bisby fellowship from the Canadian Institutes of Health Research. The authors report no competing interests.