MYOZ2

Myozenin-2, also referred to as Calsarcin-1, is a protein that in humans is encoded by the MYOZ2 gene.^[5][6][7] The Calsarcin-1 isoform is a muscle protein expressed in cardiac muscle and slow-twitch skeletal muscle, which functions to tether calcineurin to alpha-actinin at Z-discs, and inhibit the pathological cardiac hypertrophic response. This differs from the fast-skeletal muscle isoform, calsarcin-2.

MYOZ2
Identifiers
Aliases	MYOZ2, C4orf5, CMH16, CS-1, myozenin 2, FATZ-2
External IDs	OMIM: 605602; MGI: 1913063; HomoloGene: 9583; GeneCards: MYOZ2; OMA:MYOZ2 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q26 Start 119,135,832 bp[1] End 119,187,789 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 G1 Start 122,799,855 bp[2] End 122,828,664 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right ventricle myocardium of left ventricle cardiac muscle tissue of right atrium thoracic diaphragm glutes vena cava biceps brachii Skeletal muscle tissue of biceps brachii Skeletal muscle tissue of rectus abdominis right auricle of heart Top expressed in interventricular septum soleus muscle myocardium of ventricle cardiac muscles right ventricle intercostal muscle thoracic diaphragm atrioventricular valve ankle extraocular muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein phosphatase 2B binding protein binding telethonin binding actin binding FATZ binding Cellular component cytoplasm sarcomere actin cytoskeleton Z discdkac Biological process myofibril assembly biological process negative regulation of transcription by RNA polymerase II skeletal muscle tissue development skeletal muscle fiber adaptation sarcomere organization negative regulation of calcineurin-NFAT signaling cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51778 59006 Ensembl ENSG00000172399 ENSMUSG00000028116 UniProt Q9NPC6 Q9JJW5 RefSeq (mRNA) NM_016599 NM_021503 NM_001355462 RefSeq (protein) NP_057683 NP_067478 NP_001342391 Location (UCSC) Chr 4: 119.14 – 119.19 Mb Chr 3: 122.8 – 122.83 Mb PubMed search [3] [4]
Wikidata
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Structure

Calsarcin-1 is a 29.9 kDa protein composed of 264 amino acids.^[8][9] Calsarcin-1 and calsarcin-2 are only 31% homologous (94 identical amino acids), exhibiting the highest homology at N- and C-termini. Calsarcin-1 binds to alpha-actinin,^[10] gamma-filamin,^[11] telethonin,^[11] ZASP/Cypher^[11] and calcineurin.^[10] The binding region of calsarcin-1 to alpha-actinin is localized to amino acids 153-200, and that of calsarcin-1 to calcineurin is amino acids 217-240.^[10]

Function

The function of calsarcin-1 in cardiac and slow-skeletal muscle has been illuminated through studies in transgenic animals. Mice lacking the MYOZ2 gene (MYOZ2-/-) are generally sensitized to calcineurin signaling in both muscle types.^[11] In slow-skeletal muscle, MYOZ2-/- show increased slow-twitch muscle fibers. In cardiac, MYOZ2-/- show induction of the fetal gene program typical of pathologic hypertrophy, however there was no evidence of hypertrophied morphometry at baseline. However, upon calcineurin activation or pressure overload-induced pathologic hypertrophy, MYOZ2-/- exhibited exaggerated cardiac hypertrophy, demonstrating that calsarcin-1 negatively modulates the function of calcineurin during pathologic hypertrophic remodeling.^[11] Additional studies supported these findings in demonstrating that adenoviral overexpression of calsarcin-1 attenuated Gq alpha subunit-stimuated hypertrophy and ANP induction, by Angiotensin II, phenylephrine and endothelin-1 agonists in neonatal cardiomyocytes.^[12] Overexpression of calsarcin-1 in mice (CS1Tg) was protective against Angiotensin II-induced pathologic cardiac hypertrophy, evidenced by preserved fractional shortening and contractility, as well as a blunted induction of the fetal hypertrophic gene program and significantly reduced expression of calcineurin-stimulated MCIP1.4 gene expression.^[12] Taken together, these studies strongly support a role for calsarcin-1 in suppressing pathologic cardiac hypertrophy.

Clinical Significance

Two missense mutations in MYOZ2, Ser48Pro and Ile246Met, have been shown to be causal for rare forms of familial hypertrophic cardiomyopathy.^[13]