Thymopoietin (lamina-associated polypeptide 2) gene mutation associated with dilated cardiomyopathy

Thymopoietin or TMPO (indicated by its alternative gene symbol, LAP2, in this work) has been proposed as a candidate disease gene for dilated cardiomyopathy (DCM), since a LAP2 product associates with nucleoplasmic lamins A/C, which are encoded by the DCM gene LMNA. We developed a study to screen for genetic mutations in LAP2 in a large collection of DCM patients and families. A total of 113 subjects from 88 families (56 with familial DCM (FDC) and 32 with sporadic DCM) were screened for LAP2 mutations using denaturing high-performance liquid chromatography and sequence analysis. We found a single putative mutation affecting the LAP2 alpha isoform in one FDC pedigree. The mutation predicts an Arg690Cys substitution (c.2068C > T; p.R690C) located in the C-terminal domain of the LAP2 alpha protein, a region that is known to interact with lamin A/C. RT-PCR, Western blot analyses, and immunolocalization revealed low-level LAP2a expression in adult cardiac muscle, and localization to a subset of nuclei. Mutated Arg690Cys LAP2 alpha expressed in HeLa cells localized to the nucleoplasm like wild-type LAP2 alpha, with no effect on peripheral and nucleoplasmic lamin A distribution. However, the in vitro interaction of mutated LAP2 alpha with the pre-lamin A C terminus was significantly compromised compared to the wild,type protein. LAP2 mutations may represent a rare cause of DCM. The Arg690Cys mutation altered the observed LAP2 alpha interaction with A-type lamins. Our finding implicates a novel nuclear lamina,associated protein in the pathogenesis of genetic forms of dilated cardiomyopathy. Hum Mutat 26(6), 566-574, 2005. (c) 2005 Wiley-Liss, Inc.