Genetic investigations of sporadic inclusion body myositis and myopathies with structural abnormalities and protein aggregates in muscle

• Main Author: Gang, Q.
• Other Authors: Houlden, H. ; Bettencourt, C. ; Hanna, M.
• Published: University College London (University of London) 2016
• Subjects: 612.8
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.746331

The application of whole-exome sequencing (WES) has not only dramatically accelerated the discovery of pathogenic genes of Mendelian diseases, but has also shown promising findings in complex diseases. This thesis focuses on exploring genetic risk factors for a large series of sporadic inclusion body myositis (sIBM) cases, and identifying disease-causing genes for several groups of patients with abnormal structure and/or protein aggregates in muscle. Both conventional and advanced techniques were applied. Based on the International IBM Genetics Consortium (IIBMGC), the largest sIBM cohort of blood and muscle tissue for DNA analysis was collected as the initial part of this thesis. Candidate gene studies were carried out and revealed a disease modifying effect of an intronic polymorphism in TOMM40, enhanced by the APOE ε3/ε3 genotype. Rare variants in SQSTM1 and VCP genes were identified in seven of 181 patients, indicating a mutational overlap with neurodegenerative diseases. Subsequently, a first whole-exome association study was performed on 181 sIBM patients and 510 controls. This reported statistical significance of several common variants located on chromosome 6p21, a region encompassing genes related to inflammation/infection. WES was performed on a group of 35 cases with tubular aggregates/cylindrical spirals, and detected rare variants in known/candidate genes. Disease-causing genes were identified in four families with protein aggregates in muscle also by WES. In one family identified with a novel homozygous deletion in SBF1 with a rare autosomal-recessive neuromuscular condition, functional analysis was carried out indicating a loss-of-function mechanism underlying the pathogenesis of the disease. The collection of a large series of sIBM patients through the IIBMGC has been shown here to reveal important genetic findings and will be a valuable resource for the future. WES proved to be important in sIBM and also to be an efficient method to investigate the genetics basis of rare complex muscle disorders.