Alternative titles; symbols
HGNC Approved Gene Symbol: MYOZ2
Cytogenetic location: 4q26 Genomic coordinates (GRCh38) : 4:119,135,832-119,187,789 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q26 | Cardiomyopathy, hypertrophic, 16 | 613838 | Autosomal dominant | 3 |
Calcineurin (see 114105) is a calcium/calmodulin-dependent serine-threonine phosphatase that plays an important role in transducing calcium-dependent signals in a variety of cell types. Calcineurin has also been shown to have a profound influence on the properties of striated muscle cells, including cardiac muscle. To identify potential cardiac-specific regulators of calcineurin, Frey et al. (2000) conducted a yeast 2-hybrid screen, using the catalytic A subunit of calcineurin as bait. They identified a novel family of striated muscle-specific calcineurin-interacting proteins called calsarcins. Calsarcins interact and colocalize with the Z disc protein alpha-actinin (ACTN1; 102575) in vitro and in vivo and thereby tether calcineurin to the sarcomere of cardiac and skeletal muscle. These properties of calsarcins suggest an important role for these proteins in modulating the function and substrate specificity of calcineurin in striated muscle cells.
Frey et al. (2000) cloned and characterized the cDNA of calsarcin-1 and calsarcin-2 (MYOZ1; 605603). Calsarcin-1 encodes a 263-amino acid protein, which shows the highest sequence homology with calsarcin-2 in the N and C termini. Northern blot analysis of human tissues revealed a highly striated muscle-specific expression pattern of both genes. Calsarcins 1 and 2 are expressed in developing cardiac and skeletal muscle during embryogenesis, but calsarcin-1 is expressed specifically in adult cardiac and slow-twitch skeletal muscle as 1.6- and 2.6-kb transcripts, whereas calsarcin-2 is expressed only in fast skeletal muscle as a 1.6-kb transcript.
Gross (2015) mapped the MYOZ2 gene to chromosome 4q26 based on an alignment of the MYOZ2 sequence (GenBank AF249873) with the genomic sequence (GRCh38).
By yeast 2-hybrid analysis, Frey and Olson (2002) showed that ZASP (LDB3; 605906) interacted strongly with MYOZ1, MYOZ2, and MYOZ3 (610735). Coimmunoprecipitation studies in COS-7 cells showed that both the longest and shortest ZASP splice variants bind all 3 members of the myozenin family, suggesting that the interaction is not isoform specific.
In a 3-generation black family segregating autosomal dominant CMH mapping to chromosome 4q26-q27 (CMH16; 613838), Osio et al. (2007) identified a heterozygous missense mutation in the candidate gene MYOZ2 (S48P; 605602.0001) that segregated with disease in the family. Analysis of MYOZ2 in 516 additional CMH probands revealed another patient with a different heterozygous missense mutation (I246M; 605602.0002). Both mutations occurred at highly conserved residues in MYOZ2.
Frey et al. (2004) generated Myoz2 -/- mice and observed enhanced calcineurin signaling in striated muscle and an excess of slow skeletal muscle fibers. There was activation of a hypertrophic gene program despite the absence of cardiac hypertrophy in the mutant mice. The cardiac growth response to pressure overload was enhanced, but cardiac adaptation to other hypertrophic stimuli such as chronic catecholamine stimulation or exercise was not affected. Frey et al. (2004) concluded that MYOZ2 modulates calcineurin signaling in striated muscles in vivo and thereby influences the response of the heart to biomechanical stress.
Frank et al. (2007) generated Myoz2-overexpressing transgenic mice, which did not exhibit a pathologic phenotype when unchallenged. Long-term infusion of angiotensin II (see 106150) resulted in a similar degree of hypertension in both transgenic and wildtype mice; in contrast to wildtype, however, the Myoz2-overexpressing mice did not develop cardiac hypertrophy, yet had no impairment of contractile function by cardiac catheterization and echocardiography. Induction of the hypertrophic gene program was markedly blunted and expression of the calcineurin-dependent gene MCIP1 (RCAN1; 602917) was significantly reduced in transgenic mice. Frank et al. (2007) concluded that the calsarcin-1 protein prevents angiotensin II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling.
Ruggiero et al. (2013) generated transgenic mice carrying the Myoz2 S48P or I246M mutations and observed the development of cardiac hypertrophy with preserved systolic function; histologic examination revealed increased cardiac myocytes and interstitial fibrosis. Immunofluorescence staining showed colocalization of wildtype and mutant Myoz2 proteins with alpha-actinin (see 102573) at the Z discs, and electron microscopy revealed disrupted and malaligned Z discs in the mutant mice. Cardiac calcineurin (see 114105) activity was unchanged in the mutant mice compared to wildtype; however, levels of phospho-Erk1 (601795)/Erk2 (176948) were increased and levels of Jnk54/46 were reduced in transgenic mice compared to controls. Ruggiero et al. (2013) proposed that the CMH phenotype caused by MYOZ2 mutations might be independent of calcineurin activity in the heart.
In 6 affected individuals from a 3-generation black family with hypertrophic cardiomyopathy (CMH16; 613838), Osio et al. (2007) identified heterozygosity for a T-C transition at nucleotide position 15,072 in exon 3 of the MYOZ2 gene, resulting in a ser48-to-pro (S48P) substitution at a highly conserved residue. The mutation was not found in 4 clinically normal family members or in 658 controls who were asymptomatic and had normal electrocardiograms and echocardiograms, including 253 black individuals.
Ruggiero et al. (2013) generated transgenic mice carrying the Myoz2 S48P mutation and observed the development of cardiac hypertrophy with preserved systolic function; histologic examination revealed increased cardiac myocytes and interstitial fibrosis. Immunofluorescence staining showed colocalization of wildtype and mutant Myoz2 proteins with alpha-actinin (see 102573) at the Z discs, and electron microscopy revealed disrupted and malaligned Z discs in the mutant mice.
In a patient with hypertrophic cardiomyopathy (CMH16; 613838), Osio et al. (2007) identified heterozygosity for an A-G transition at nucleotide position 50,278 in exon 6 of the MYOZ2 gene, resulting in an ile246-to-met (I246M) substitution at a highly conserved residue. The patient had 2 deceased sibs with CMH. The mutation was not found in 2 unaffected offspring or in 517 unaffected controls, including 405 white individuals.
Ruggiero et al. (2013) generated transgenic mice carrying the Myoz2 I246M mutation and observed the development of cardiac hypertrophy with preserved systolic function; histologic examination revealed increased cardiac myocytes and interstitial fibrosis. Immunofluorescence staining showed colocalization of wildtype and mutant Myoz2 proteins with alpha-actinin (see 102573) at the Z discs, and electron microscopy revealed disrupted and malaligned Z discs in the mutant mice.
Frank, D., Kuhn, C., van Eickels, M., Gehring, D., Hanselmann, C., Lippl, S., Will, R., Katus, H. A., Frey, N. Calsarcin-1 protects against angiotensin-II-induced cardiac hypertrophy. Circulation 116: 2587-2596, 2007. Note: Erratum: Circulation 117: e19 only, 2008. [PubMed: 18025526] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.711317]
Frey, N., Barrientos, T., Shelton, J. M., Frank, D., Rutten, H., Gehring, D., Kuhn, C., Lutz, M., Rothermel, B., Bassel-Duby, R., Richardson, J. A., Katus, H. A., Hill, J. A., Olson, E. N. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nature Med. 10: 1336-1343, 2004. [PubMed: 15543153] [Full Text: https://doi.org/10.1038/nm1132]
Frey, N., Olson, E.N. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J. Biol. Chem. 277: 13998-14004, 2002. [PubMed: 11842093] [Full Text: https://doi.org/10.1074/jbc.M200712200]
Frey, N., Richardson, J. A., Olson, E. N. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc. Nat. Acad. Sci. 97: 14632-14637, 2000. [PubMed: 11114196] [Full Text: https://doi.org/10.1073/pnas.260501097]
Gross, M. B. Personal Communication. Baltimore, Md. 4/24/2015.
Osio, A., Tan, L., Chen, S. N., Lombardi, R., Nagueh, S. F., Shete, S., Roberts, R., Willerson, J. T., Marian, A. J. Myozenin 2 is a novel gene for human hypertrophic cardiomyopathy. Circ. Res. 100: 766-768, 2007. [PubMed: 17347475] [Full Text: https://doi.org/10.1161/01.RES.0000263008.66799.aa]
Ruggiero, A., Chen, S. N., Lombardi, R., Rodriguez, G., Marian, A. J. Pathogenesis of hypertrophic cardiomyopathy caused by myozenin 2 mutations is independent of calcineurin activity. Cardiovasc. Res. 97: 44-54, 2013. [PubMed: 22987565] [Full Text: https://doi.org/10.1093/cvr/cvs294]