A novel gene for hypertrophic cardiomyopathy

The disorder is the most common cause of sudden cardiac death in people aged younger than 36 years.

Hypertrophic cardiomyopathy is a genetic disorder characterized by hypertrophy, cardiac fibrosis and myocyte disarray. The latter feature is considered to be the pathognomonic feature that separates it from other forms of hypertrophy.

The disorder is the most common form of inherited cardiac abnormality, with a gene frequency of one in 500, and also the most common cause of sudden cardiac death in people aged younger than 36. Given the frequency of mutations for hypertrophic cardiomyopathy, it amounts to a prevalence in the world population of more than 12 million. In the United States alone, there are more than 600,000 individuals with a mutant gene that could induce hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy has also served as a paradigm for studying many of the features of cardiac hypertrophy and HF. In the 1990s, the first gene was identified to be a mutation in the cardiac myosin heavy chain. Since that time, 12 other genes have been identified, accounting for more than 500 mutations responsible for this disease. Although new mutations in the known genes are being reported on an annual basis, there has not been a new gene reported for hypertrophic cardiomyopathy for nearly a decade.

Robert Roberts

Myozenin 2 gene

In a recent issue of Circulation Research, Osio et al reported on a novel gene, myozenin 2, responsible for hypertrophic cardiomyopathy in two families with the disorder. The work was performed in the laboratory of A.J. Marian, MD, at Baylor College of Medicine.

A novel approach was taken to identify the new gene, which may help to identify other novel genes in the future. Essentially, all of the genes identified that induce hypertrophic cardiomyopathy encode sarcomeric proteins. Thus, any sarcomeric protein is a good candidate.

There are several genes known that encode for sarcomeric proteins with known chromosomal location. Selecting such genes and knowing chromosomal markers in close proximity (referred to as a haplotype), one can determine if such haplotypes segregate with members of a family with hypertrophic cardiomyopathy and not with the clinically normal family members.

Using this approach, we identified a family in which a haplotype containing the sarcomeric gene myozenin 2 was shown to segregate with the members in the family with hypertrophic cardiomyopathy but not with clinically normal family members. Following this observation, it was then possible to clone the region to determine which genes were there. Myozenin 2 was the better candidate that was cloned, sequenced and the mutation identified, which was found only in affected individuals.

The mutation is a missense mutation in which thymidine was substituted for cytosine at nucleotide position 15,072. In the protein, this led to substitution of serine to proline at amino acid 48. Mutation was present in all six affected members and absent in the four clinically normal members. It is of note that in this family, two of the affected individuals are dizygotic twin brothers, and both have the mutation. The mutation was also absent in 658 clinically normal individuals.

The serine substituted by proline was shown to be a highly conserved amino acid across several species. Since many of the families identified are small and not amenable to identifying or localizing the gene by conventional genetic linkage analysis, the haplotype approach may identify several of the genes in those families in which mutation has yet to be identified.

In an attempt to identify whether other patients also have mutation in myozenin 2, we screened 560 probands by direct sequencing. Another heterozygous missense mutation was identified in which arginine was substituted by guanine at nucleotide 50,278 in a proband with two siblings.

The mutation induced a change in the protein at amino acid 246 in which isoleucine, a highly conserved amino acid, was substituted for methionine. It was present in one of the 516 probands, absent in two clinically normal family members, and absent in 517 controls. Thus, both mutations affected highly conserved amino acids and it was concluded that the gene was a novel causal gene for human hypertrophy cardiomyopathy. However, since it was present in such a small percentage of the individuals screened, it would appear to be an uncommon cause for hypertrophy cardiomyopathy.

This brings a total number of genes identified to be responsible for hypertrophic cardiomyopathy to 14. It remains that myosin heavy chain, myosin-binding protein C and troponin T account for 60% to 70% of all cases known to be due a mutation.

Other effects of myozenin 2

The myozenin 2 gene encodes for a protein that is well recognized to be a part of the Z-disk of the sarcomere. Another name for myozenin 2 is calsarcin-1. Myozenins are Z-disk proteins that are found exclusively in striated muscle, which includes the heart and slow skeletal muscle fibers.

Myozenin 2 is a negative regulator of calcineurin function. In the mouse, deletion of myozenin 2 leads to activation of calcineurin, nuclear localization of NAFT, expression of cardiac hypertrophic genes and enhanced cardiac hypertrophic response. Thus, it would appear that myozenin 2 mutations cause hypertrophy by activating the calcineurin pathway.

Despite this obvious conclusion, the two mutations identified do not affect the known binding domain for calcineurin or the known binding domain for alpha-actinin. Nevertheless, these mutations in some way alter calcineurin signaling and/or binding to alpha-actinin, such as by changing the secondary structure.

Another Z-disk protein has previously been identified to be the cause of hypertrophic cardiomyopathy, namely the T-cap — telethonin. It is likely that both of these proteins act through a common mechanism to induce hypertrophic cardiomyopathy. It remains to be identified as to the precise mechanism whereby myozenin 2 mutations induce hypertrophic cardiomyopathy, however.

In summary, two mutations in myozenin 2 have been identified to be responsible for familial hypertrophic cardiomyopathy. The continual pursuit of genes responsible for hypertrophic cardiomyopathy will not only add to our list for genetic screening, but also will ultimately further elucidate the function of sarcomeric proteins in the physiology and pathology of the heart.

Robert Roberts, MD, is President and CEO of the University of Ottawa Heart Institute and Section Editor of the Molecular Cardiology Section of the Cardiology Today Editorial Board.

For more information:

• Osio A, Tan L, Chen SN, et al. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ Res. 2007;100:766-768.