Abstract
Dilated cardiomyopathy (DCM) is characterized by cardiac dilation and systolic dysfunction. So far sixteen genes have been shown to cause autosomal dominant familial dilated cardiomyopathy (FDC). We identified a large Korean family from the Jeju island showing a clear Mendelian inheritance of FDC. A genomewide linkage scan at 9 cM marker density identified a peak multipoint LOD score of 2.82 at D1S195. Haplotyping of the region with 15 additional markers defined a candidate interval that included a known candidate gene encoding the lamin A/C (LMNA). Sequencing of the LMNA exons revealed one missense mutation at C568T (Arg190Trp) in the alpha-helical rod domain of the LMNA gene co-segregating with FDC with conduction-system disease. The same mutation was found in patients of another Korean family with FDC without conduction-system disease. Upon screening 14 sporadic DCM cases, we found three LMNA mutations including a case having a previously described (Glu161Lys) mutation and two having novel mutations (Glu53Val and Glu186Lys). Our results suggest that variable genotypes of laminopathy are implicated in not only familial but also considerable proportion of sporadic DCM.
Highlights
Dilated cardiomyopathy (DCM) characterized by cardiac dilation and systolic dysfunction represents a heterogeneous group of inherited and acquired disorders
Among the 16 mutated genes associated with DCM, the human nucleoplasmic lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy
In the present study we performed a linkage analysis followed by a candidate gene screening to localize the disease gene in a Korean family affected with an autosomal dominant severe DCM with conduction-system disease
Summary
Dilated cardiomyopathy (DCM) characterized by cardiac dilation and systolic dysfunction represents a heterogeneous group of inherited and acquired disorders (for review, see Ahmad et al, 2005; Burkett and Hershberger, 2005). Among the 16 mutated genes associated with DCM, the human nucleoplasmic lamin A/C (LMNA) gene has been reported in forms associated with conduction-system disease with or without skeletal muscle myopathy. By a mutation screen of the coding sequence of the LMNA gene on all family members, we identified a previously described missense mutation (Arg190Trp) in the rod domain of the LMNA gene that cosegregated with the disease in the family. We found the same mutation in patients of another Korean family with FDC without conduction-system disease. Ten mutations (R60G, L85R, K97E, E111X, E161K, Arg190Trp, N195K, E203G, E317K, R377H) in the rod domain of the LMNA gene were reported to be associated with DCM through disorganization of the lamina (Fatkin et al, 1999; Arbustini et al, 2002; Sebillon et al, 2003). Our results show that LMNA mutations are associated with FDC and DCM in Koreans
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