Pathogenesis of Unexplained Drowning: New Insights From a Molecular Autopsy

Tester, David J.; Kopplin, Laura J.; Creighton, Wendy; Burke, Allen P.; Ackerman, Michael J.
May 2005
Mayo Clinic Proceedings;May2005, Vol. 80 Issue 5, p596
Academic Journal
OBJECTIVE: To perform a molecular autopsy Involving the RyR2-encoded cardiac ryanodine receptor/calcium release channel to determine whether mutations responsible for catecholaminergic polymorphic ventricular tachycardla (CPVT) represent a novel pathogenic basis for unexplained drownings. METHODS: A cardiac channel molecular autopsy was performed on 2 individuals who died of unexplained drowning and whose cases were referred to the Sudden Death Genomics Laboratory at the Mayo Clink in Rochester Minn. Comprehensive mutational analysis of all 60 protein-encoded exons of the 5 long QT syndrome- causing cardiac channel genes and a targeted analysis of 18 RyR2 exons known to host RyR2-medilated CPVT-causing mutations (CPVT1) was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. RESULTS: Both Individuals harbored novel mutations In RyR2. Postmortem mutational analysis revealed a familial missense mutation in non 14, R414C, in a 16-year-old girl. A 9-year-old boy possessed a sporadic missense mutation in exon 49, V2475F. Both amino acid positions involve highly conserved residues that localize to critical functional domains in the calcium release channel. Neither substitution was present in 1000 reference shies. CONCLUSIONS: This molecular autopsy study provides proof of principle that RyR2 mutations can underlie some unexplained drownings. A population-based genetic epidemiology study that Involves molecular autopsies of individuals who die of unexplained drowning Is needed to determine the prevalence and spectrum of KCNQ1 and now RyR2 mutations as potential pathogenic mechanisms for drowning.


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