MYPN – Dilated Cardiomyopathy

Autosomal dominant variants in MYPN have been implicated in dilated cardiomyopathy (DCM), characterized by left ventricular dilatation and systolic dysfunction. Initial screening in 255 familial and sporadic DCM cases identified two heterozygous missense mutations, c.2863C>T (p.Arg955Trp) and c.2882C>T (p.Pro961Leu), absent from 300 controls (PMID:22892539). Subsequent targeted sequencing in 21 DCM patients revealed one additional proband with c.1888G>A (p.Glu630Lys) (PMID:26458567). Screening of 114 DCM patients uncovered four heterozygous probands—two familial (R1088H, I83fsX105) and two sporadic (V1195M, P1112L)—with absent variants in 400 controls (PMID:18006477). A transgenic mouse model and comparative immunohistochemistry demonstrated that the c.59A>G (p.Tyr20Cys) variant leads to disrupted myofibrillar architecture and impaired nuclear shuttling in cardiomyocytes (PMID:22286171).

Overall, eight unrelated probands with heterozygous MYPN variants have been reported, including two families with confirmed segregation. Multiple missense changes localize to α-actinin–binding and immunoglobulin-like domains, with no recurrent founder alleles identified. Functional studies reveal haploinsufficiency and dominant-negative effects: immunolocalization shows reduced Z-line MYPN, transfected cardiomyocytes display sarcomere disorganization and cell death, and Y20C transgenic mice develop cardiomyopathy with altered CARP binding and intercalated disc disarray.

No studies have refuted the association or provided alternative mechanisms. Collectively, the genetic data and robust functional concordance support a moderate clinical validity for MYPN in DCM. MYPN variant testing may inform diagnostic evaluation and familial risk assessment in dilated cardiomyopathy.

References

• European journal of human genetics • 2013 • Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy. PMID:22892539
• International journal of molecular medicine • 2015 • Targeted next-generation sequencing of candidate genes reveals novel mutations in patients with dilated cardiomyopathy. PMID:26458567
• Cardiovascular research • 2008 • Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. PMID:18006477
• Human molecular genetics • 2012 • Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. PMID:22286171

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