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Dilated cardiomyopathy: a genetically heterogeneous disease

2002; Elsevier BV; Volume: 360; Issue: 9334 Linguagem: Inglês

10.1016/s0140-6736(02)09879-3

1474-547X

Tony Shaw, Perry Elliott, William J. McKenna,

RNA Research and Splicing

Dilated cardiomyopathy (DCM) is the most common cause of congestive heart failure in the young. It is generally transmitted in an autosomal dominant manner although X-linked, autosomal recessive, and mitochondrial inheritance are also seen. 1 Towbin JA Berul CI Towbin JA The molecular genetics of cardiac electrophysiological disease. Kluwer Academic, Norwell MA2000: 195-218 Google Scholar , 2 Grunig E Tasman JA Kucherer H Franz W Kubler W Katus HA Frequency and phenotypes of familial dilated cardiomyopathy.. J Am Coll Cardiol. 1998; 31: 186-194 Crossref PubMed Scopus (351) Google Scholar The genetic heterogeneity of DCM is illustrated by the autosomal dominant form with several loci and gene mutations identified: 1q32 (cardiac troponin T), 2q31, 2q35 (desmin), 4q12 (β-sarcoglycan), 5q33 (δ-sarcoglycan), 9q13-22, 10q21–23, 14q11 (β-myosin heavy chain), 15q2 (δ-tropomyosin), and 15q14 (actin). DCM also occurs with cardiac conduction-system disease (1q21, lamin A/C). In the X-linked form the loci Xp21 (dystrophin) and Xq28 (tafazzin) have been identified. Timothy Olson and colleagues 3 Olson TM Illenberger S Kishimoto NY Huttelmaier S Keating MT Jockusch BM Metavinculin mutations alter actin interaction in dilated cardiomyopathy.. Circulation. 2002; 105: 431-437 Crossref PubMed Scopus (218) Google Scholar recently identified vinculin as a DCM gene. The vinculin gene maps to 10q22·1-10q23, a known locus for DCM. The panel shows some proteins involved in DCM and their cellular location. Although many mutations causing DCM have been identified the mechanisms by which individual mutations cause the disease are not well understood. Starting from nucleus both RXRα and CREB have been implicated in DCM. Mutations in genes encoding nuclear lamin A/C and intermediate filament protein, desmin, are known to cause DCM. Desmin is found in Z-line of sarcomere and in intercalated discs joining cardiomyocytes. Simplified sarcomere is shown to highlight positions of thick and thin filaments relative to Z-line, which is shown in more detail. Intercalated disc is shown without characteristic stepped profile, desmosomes, and gap junctions for clarity. MLP=muscle LIM protein, CREB=cyclic-AMP response element binding-protein, nNOS=neuronal nitric oxide synthase, RXRα=retinoid X receptor alpha. Adapted from ref 6, with permission. Adapted from ref 6 (http://www.nature.com/nature) Starting from nucleus both RXRα and CREB have been implicated in DCM. Mutations in genes encoding nuclear lamin A/C and intermediate filament protein, desmin, are known to cause DCM. Desmin is found in Z-line of sarcomere and in intercalated discs joining cardiomyocytes. Simplified sarcomere is shown to highlight positions of thick and thin filaments relative to Z-line, which is shown in more detail. Intercalated disc is shown without characteristic stepped profile, desmosomes, and gap junctions for clarity. MLP=muscle LIM protein, CREB=cyclic-AMP response element binding-protein, nNOS=neuronal nitric oxide synthase, RXRα=retinoid X receptor alpha. Adapted from ref 6, with permission. Adapted from ref 6 (http://www.nature.com/nature)