Cardiomyopathy, Dilated, 1g

A number sign (#) is used with this entry because of evidence that autosomal dominant dilated cardiomyopathy-1G (CMD1G) is caused by heterozygous mutation in the titin gene (TTN; 188840) on chromosome 2q31.

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see CMD1A (115200).

Mapping

Siu et al. (1999) clinically evaluated 3 generations of a Native American kindred with autosomal dominant transmission of dilated cardiomyopathy. Nine surviving affected individuals had early-onset disease (ventricular chamber dilatation during the teenage years and congestive heart failure during the third decade of life). The disease was nonpenetrant in 2 obligate carriers. By linkage analysis, Siu et al. (1999) identified a novel disease locus at marker D2S1244 on 2q31 (maximum lod = 4.06 at theta = 0.0) between the glucagon gene (138030) and marker D2S72; they designated this locus CMD1G. Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, the authors analyzed sequences encoding 900-amino acid residues of the cardiac-specific (N2-B) domain of the gene. Although 5 sequence variants were identified, none segregated with the disease in this family.

Molecular Genetics

In 2 unrelated families with autosomal dominant dilated cardiomyopathy, Gerull et al. (2002) identified 2 different heterozygous mutations in the titin gene (188840.0002; 188840.0003). Both families showed reduced penetrance and no involvement of noncardiac muscle. The latter was surprising since exons of TTN that contain the 2 CMD-causing mutations are both expressed in cardiac and noncardiac muscle isoforms.

In 4 patients with dilated cardiomyopathy, Itoh-Satoh et al. (2002) identified 4 different mutations in the TTN gene (188840.0007-188840.0010). Two of the cases were familial.

Herman et al. (2012) used next-generation sequencing to analyze the TTN gene in 203 individuals with dilated cardiomyopathy, 231 with hypertrophic cardiomyopathy (CMH), and 249 controls. The frequency of TTN mutations was significantly higher among individuals with CMD (27%) than among those with CMH (1%) or controls (3%). In CMD families, TTN mutations cosegregated with dilated cardiomyopathy, with highly observed penetrance (greater than 95%) after the age of 40 years. Mutations associated with CMD were overrepresented in the titin A-band but were absent from the Z-disc and M-band regions of titin. Overall, rates of cardiac outcomes were similar in individuals with or without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers. Herman et al. (2012) concluded that TTN truncating mutations are the most common known genetic cause of dilated cardiomyopathy, occurring in approximately 25% of familial CMD cases and in 18% of sporadic cases.

Pathogenesis

In assays of contractile function using cardiac microtissues (CMTs) engineered from human induced pluripotent stem (iPS) cells, Hinson et al. (2015) found that, like TTN-truncating variants (TTNtvs), certain missense mutations (e.g., W976R, 188840.0003) diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, Hinson et al. (2015) explained why truncations in the A-band domain of TTN cause dilated cardiomyopathy, whereas truncations in the I-band are better tolerated. Finally, the authors demonstrated that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Hinson et al. (2015) concluded that titin mutations cause dilated cardiomyopathy by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.