Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052672.97759.36
© 2003 American Heart Association, Inc.
Clinical Research |
Compound Heterozygosity for Mutations (W156X and R225W) in SCN5A Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System
From the Experimental and Molecular Cardiology Group (C.R.B., A.A.M.W.), the Department of Clinical Genetics (C.R.B., M.M.A.M.M.), the Department of Cardiovascular Pathology (A.C.v.d.W.), and the Department of Pediatric Cardiology (J.L.), Academic Medical Center, Amsterdam, and the Department of Medical Physiology (M.B.R., W.A.G., L.J.H., H.J.), University Medical Center, Utrecht, The Netherlands.
Correspondence to Arthur A.M. Wilde, Dept of Experimental Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail a.a.wilde{at}amc.uva.nl
Cardiac conduction defects associate with mutations in SCN5A, the gene encoding the cardiac Na+ channel. In the present study, we characterized a family in which the proband was born in severe distress with irregular wide complex tachycardia. His older sister died at 1 year of age from severe conduction disease with similarly widened QRS-complexes. Mutational analysis of SCN5A in the proband demonstrated compound heterozygosity for a nonsense mutation (W156X), inherited from the father, and a missense mutation (R225W), inherited from the mother. Genotyping on DNA extracted from tissue from the deceased sibling revealed the same SCN5A genotype. Injection of cRNA encoding the W156X mutation in Xenopus oocytes did not produce any current. The R225W substitution neutralizes the third Arg residue within the voltage-sensing segment of domain I. Expression studies showed that this mutation leads to a severe reduction in INa and is also associated with gating changes. Histological examination of the heart from the deceased sibling revealed changes consistent with a dilated type of cardiomyopathy and severe degenerative abnormalities of the specialized conduction system. The occurrence of compound heterozygosity for these two mutations implies that the proband carries solely severely dysfunctional cardiac Na+ channels. This explains his severe phenotype and that of his deceased sister who had been a carrier of the same genotype. The morphological changes within the heart of the deceased sibling may have occurred secondary to the Na+ channel abnormality and contributed to the severity of the disorder in this individual.
Key Words: arrhythmia • conduction • ion channels • electrophysiology • cardiomyopathy
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