MYOZ2 – Hypertrophic cardiomyopathy

Myozenin 2 is a Z-disc protein that regulates calcineurin activity in cardiomyocytes. Heterozygous missense variants in MYOZ2 underlie autosomal dominant Hypertrophic cardiomyopathy, characterized by left ventricular hypertrophy, fibrosis and risk of sudden death.

In a linkage study of a six-member kindred, a T→C transition at nucleotide c.142T>C (p.Ser48Pro) cosegregated with HCM (LOD 2.03) and was absent in 658 controls (PMID:17347475). Screening of 516 additional probands identified a second missense c.738A>G (p.Ile246Met) in an unrelated individual (PMID:17347475).

A five-generation pedigree of 74 members exhibited genetic anticipation with decreasing ages of onset and increased severity, along with an accumulation of MYOZ2 variants in younger generations (PMID:28296734).

To date, all reported pathogenic alleles in MYOZ2 are missense substitutions affecting key Z-disc interaction domains; no loss-of-function or splice variants have been implicated.

Transgenic mice expressing human MYOZ2 p.Ser48Pro or p.Ile246Met on a hemizygous background develop cardiomyocyte hypertrophy, interstitial fibrosis and Z-disc disarray with preserved systolic function. These phenotypes occur without altered calcineurin activity, supporting a dominant-negative or gain-of-function mechanism disrupting sarcomeric integrity (PMID:22987565).

Collectively, two independent missense variants with segregation in a multi-member pedigree, recurrence in unrelated probands, and concordant transgenic models support a Moderate clinical validity for MYOZ2 in autosomal dominant HCM. MYOZ2 genetic testing may guide diagnosis, risk stratification and family screening.

References

• Medicine • 2017 • Genetic anticipation in a special form of hypertrophic cardiomyopathy with sudden cardiac death in a family with 74 members across 5 generations. PMID:28296734
• Circulation research • 2007 • Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. PMID:17347475
• Cardiovascular research • 2013 • Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. PMID:22987565

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