A.P.7: Misfolding of fibronectin III 119 subdomain in titin results in hereditary myopathy with early respiratory failure

Abstract

Hereditary myopathy with early respiratory failure (HMERF) is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. These protein aggregates are composed of multiple proteins including titin, aB-crystallin, actin, myotilin, desmin and others. Previous reports have described mutations in A-band titin ( TTN ) gene associated with HMERF. All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif of the 11-element motif A-band super-repeat. Based on the pathological findings in HMERF of protein aggregates in muscle fibers, we investigated if disease-causing mutations affect the biochemical behavior of this titin domain. All five disease-causing amino acid changes analyzed by us (p.P30068R, p.C30071R, p.W30088R, p.W30088C and p.P30091L) resulted in impaired FN3 119 domain solubility. In contrast, amino acid changes associated with common SNPs (p.V30076I, p.R30107C and p.S30125F) did not have this effect. In silico analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. Our results suggest that HMERF is caused by defective protein folding. We speculate that the FN3 119 domain could be important for protein–protein interaction that could explain why all identified mutations causing HMERF are located in this particular domain.