Dilated Cardiomyopathy (DCM)

Defects in heart development at E9.0 caused by unformed sarcomeres in titin deficient embryos. Top: scanning electron microscopy of wildtype (WT) and knockout (KO) animals at E9.0. Note the enlarged heart region and the reduced body size of KO animals in comparison to WT. Bottom: ultrastructural analysis of cardiac sarcomere maturation of wildtype (WT) and knockout (KO) hearts at E9.0. In WT hearts regular sarcomeres are formed, in contrast to unformed sarcomeres in titin deficient hearts. v, common ventricular chamber; bc, bulbus cordis; a, atrial chamber; Z, Z-disc; M, M-band; J, cellular junctions.

Mutations in the giant filament titin cause DCM in men and mice.

Familial DCM is a genetic disorder of the myocardium with progressive dilatation of the left or both ventricles. In large DCM families, positional candidate efforts have previously led to the identification of mutations in titin (TTN) associated with non-syndromic DCM. TTN encodes for the largest known protein found so far in nature. It serves as a scaffold in the sarcomere, plays a role in myofilament turnover and, in myocyte signal transduction. In one of the families we identified a segregating 2bp insertion mutation (c.43628insAT) which causes a frame shift, thereby truncating A-band titin. The 2bp insertion mutation in human exon 326 has been cloned and introduced into the mouse genome. Homozygous mice die in utero before ED9.0 (Fig.) and heterozygous mice recapitulate the human DCM phenotype.

Two additional TTN mutations were identified: a missense mutation (W930R), and another frameshift mutation (K20963fsX20972), which results in a premature stop codon. Due to its enormous size and multiple functions titin is a prominent target for mutations and may account for a significant proportion of the genetic etiology of familial DCM.

Project Related Publications

Gerull B, Atherton J, Geupel A, Sasse-Klaassen S, Heuser A, Frenneaux M, McNabb M, Granzier H, Labeit S, Thierfelder L. Identification of a novel frameshift mutation in the giant TTN in a large Australian family with dilated cardiomyopathy. J Mol Med. 2006 Jun;84(6):478-83.

Gerull B, Gramlich M, Atherton J, McNabb M, Trombitás K, Sasse-Klaassen S, Seidman JG, Seidman CE, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002; Feb;30(2):201-4.

Involved Scientists

Michael Gramlich (Postdoc)

Brenda Gerull (Postdoc)