PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA).
BACKGROUND
Plakophilin2 (PKP2) is a desmosome-related protein with numerous armadillo repeats and has been linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). Fatal arrhythmias resulting in sudden death also occur in the absence of morphologic cardiac abnormalities at autopsy, and have been linked to ion channel mutations in a subset of cases, but so far not to PKP2.


RESULTS
We sequenced all 14 exons of PKP2 in DNA extracted from postmortem heart tissues of 25 patients dying from ARVC and 25 from sudden unexpected death with negative autopsy (SUDNA). The primers were designed using the Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130XL Genetic Analyzer. Mutation damage prediction was made using Mutation Taster, Polyphen and SIFT software. In 6 of the 25 ARVC samples, 6 PKP2 mutations were identified, 4 of which were likely significant, and 3 of which were novel (p.N641del, p.L64PfsX22, p.G269R). In 6 of the 25 cases of SUDNA samples, 6 PKP2 mutations were identified, 3 of which were likely significant, and 4 of which were not previously described (p.P665S, p.Y217TfsX45, p.E540, p.S615T).


CONCLUSIONS
PKP2 mutations are not specific for ARVC and may result in SUDNA. The link between ARVC and desmosomal mutations may not be causal but related to an association between defective desmosomal proteins and arrhythmias.
Department of Forensic Medicine, Shanghai Medical College, Fudan University, Shanghai, China.
Mingchang
M
Zhang
Fabio
F
Tavora
Joao Bosco
JB
Oliveira
Ling
L
Li
Marcello
M
Franco
David
D
Fowler
Ziqin
Z
Zhao
Allen
A
Burke
D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000150:complications* / Q000235:genetics*; D001344:Autopsy; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D003896:Desmosomes / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D015994:Incidence; D008297:Male; D009154:Mutation / Q000235:genetics*; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
C495337:PKP2 protein, human; D051191:Plakophilins