Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20–30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner–nuclear membrane proteins1. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity2. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc–I-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.
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We are grateful to the families and their referring physicians. We thank R. Kühn, C. Witt, K. Rohde, L. Fitzpatrick, S. Milan and J. Müller for technical assistance. This work was supported by grants from Deutsche Herzstiftung e.V. (L.T.), Deutsche Forschungsgemeinschaft (S.L.) and from the National Institutes of Health (H.G.). The continued support of L.T. by R. Dietz (Charité, Humboldt University, Berlin) is greatly appreciated.
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Journal of Internal Medicine (2019)
JCI Insight (2019)
European Journal of Medical Genetics (2019)
Nature Reviews Disease Primers (2019)