Cardiomyopathy, Dilated, 1hh

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1HH is caused by heterozygous mutation in the BAG3 gene (603883) on chromosome 10q26.11.

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

Norton et al. (2011) reported 17 individuals from 8 families with dilated cardiomyopathy who carried heterozygous mutations in the BAG3 gene. The age at onset or diagnosis of the CMD phenotype ranged from 21 years to 64 years (median, 44). Disease severity varied considerably: although 9 of the 17 mutation carriers with CMD underwent heart transplant or died with advanced heart failure, there were 4 mutation carriers who had no disease and 1 who was asymptomatic with only mild left ventricular dysfunction. Norton et al. (2011) noted that similar phenotypic variability had been widely seen in pedigrees with CMD due to mutation in various genes.

In a large 3-generation family segregating autosomal dominant dilated cardiomyopathy and that was negative for mutation in 15 known CMD-associated genes, Norton et al. (2011) performed whole-exome sequencing and genomewide analysis of copy number variation and identified an 8,733-bp deletion in the BAG3 gene (603883.0002) that was present in all 7 affected family members and absent from 355 controls. Norton et al. (2011) then sequenced exons 2, 3, and 4 of BAG3 in an additional 311 CMD probands who were also negative for mutation in 15 known CMD-associated genes, and identified heterozygous point mutations in 7 unrelated probands that were not found in 2,644 control chromosomes (see, e.g., 603883.0003-603883.0006). Knockdown of bag3 in a zebrafish model recapitulated CMD and heart failure.

Arimura et al. (2011) analyzed the BAG3 gene in 72 Japanese probands with familial CMD and identified heterozygosity for 2 missense mutations in 2 probands: R218W (603883.0007) and L462P (603883.0008). Functional studies at the cellular level showed that these CMD-associated mutations impaired the Z-disc assembly and increased sensitivities to stress-induced apoptosis.