Characterization of the human nebulette gene: a polymorphism in an actin-binding motif is associated with nonfamilial idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled h eart with systolic dysfunction of unknown etiology. Because abnormalities i n genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence vari ations were searched for in Japanese patients with IDC and healthy controls . The nebulette gene consists of 28 exons, and four sequence variations lea ding to amino acid replacement (GLn187His, Met351Val, Asn654Lys, and Thr728 Ala) were identified in the patients. These variations were also found in t he healthy controls and hence they were polymorphisms and not disease-speci fic mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozy gotes for Lys at codon 654, a variant at a relatively conserved residue in an actin-binding motif, was significantly increased in nonfamilial IDC pati ents (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1. 21%, OR=6.25, P=0.002, 95% CI=1.92-20.29), while this association was not f ound in familial IDC patients (n=24). These observations suggest that the n ebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.