title: Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system.
abstract: 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 I(Na) 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.
authors.affiliation: Experimental and Molecular Cardiology Group, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
authors.forename: W Antoinette
authors.initials: WA
authors.lastname: Groenewegen
authors.forename: Lucas J
authors.initials: LJ
authors.lastname: Herfst
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Jan
authors.initials: J
authors.lastname: Lam
authors.forename: Habo J
authors.initials: HJ
authors.lastname: Jongsma
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology*; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D006239:Haplotypes; D006329:Heart Conduction System / Q000503:physiopathology*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000503:physiopathology; D008297:Male; D008845:Microinjections; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013610:Tachycardia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D014981:Xenopus
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels