TMPO – Dilated Cardiomyopathy

Thymopoietin (TMPO; LAP2) has been investigated as a candidate gene for autosomal dominant dilated cardiomyopathy (DCM). In a cohort of 113 DCM patients (56 familial, 32 sporadic) from 88 families, a single heterozygous TMPO variant c.2068C>T (p.Arg690Cys) was identified in one familial DCM pedigree (1 proband) without further segregation details (PMID:16247757). Subsequent screening of 25 unrelated DCM patients revealed no additional TMPO mutations (PMID:20127487). These findings suggest that TMPO variants are rare in DCM and provide limited genetic support for causality.

Functional assays have demonstrated that p.Arg690Cys does not alter nuclear localization but significantly impairs binding of LAP2α to pre-lamin A/C in vitro (PMID:16247757). Protein modeling and leukocyte nuclear morphology studies further indicate that Arg690Cys destabilizes the LAP2α homodimer and modifies nuclear shape, especially in combination with LMNA truncation (PMID:36362411). Despite moderate functional concordance, the lack of replication and segregation data limits clinical validity. Key take-home: TMPO/Arg690Cys represents a rare variant with moderate functional evidence but insufficient genetic support for routine DCM testing.

References

• Human mutation • 2005 • Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy. PMID:16247757
• Basic research in cardiology • 2010 • Genetic and ultrastructural studies in dilated cardiomyopathy patients: a large deletion in the lamin A/C gene is associated with cardiomyocyte nuclear envelope disruption. PMID:20127487
• International journal of molecular sciences • 2022 • Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys).* PMID:36362411

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