Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.

Mark M. Awad, Darshan Dalal, Crystal Tichnell, Cynthia Anne James, April Tucker, Theodore Abraham, Philip J Spevak, Hugh Calkins, Daniel P. Judge

Research output: Contribution to journalArticle

Abstract

Arrhythmogenic right ventricular dysplasia (ARVD) is a genetic disorder resulting in fibro-fatty replacement of right ventricular myocytes and consequent ventricular arrhythmias. Heterozygous mutations in PKP2 encoding plakophilin-2 have previously been reported to cause dominant ARVD with reduced penetrance. We report the first case of recessive ARVD caused by mutations in PKP2. Candidate gene analysis in a typical proband with this disorder identified a novel homozygous mutation in PKP2 (c.[2484C>T]+[2484C>T]), which is predicted to be translationally silent (p.Gly828). Analysis of the proband's mRNA, however, shows that this mutation causes predominantly cryptic splicing, with a 7-nucleotide deletion in exon 12. The ensuing frame shift disrupts the last 54 amino acids of plakophilin-2 and extends the open reading frame by 145 nucleotides (48 amino acids) into the 3' untranslated region. Haplotype analysis demonstrates the absence of remote consanguinity. Heterozygous family members produce approximately 60% of properly spliced PKP2 and do not have manifestations of ARVD. Further analysis of PKP2 mRNA sequence revealed two additional alternatively spliced transcripts. The possibility of cryptic or alternative splicing should be considered with identification of apparently synonymous nucleotide substitutions in this gene. (c) 2006 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)1157
Number of pages1
JournalHuman Mutation
Volume27
Issue number11
StatePublished - Nov 2006

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Arrhythmogenic Right Ventricular Dysplasia
Plakophilins
Mutation
Nucleotides
Consanguinity
Amino Acids
Messenger RNA
Inborn Genetic Diseases
Penetrance
Alternative Splicing
Genetic Association Studies
3' Untranslated Regions
Muscle Cells
Haplotypes
Open Reading Frames
Cardiac Arrhythmias
Exons
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Awad, M. M., Dalal, D., Tichnell, C., James, C. A., Tucker, A., Abraham, T., ... Judge, D. P. (2006). Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Human Mutation, 27(11), 1157.

Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. / Awad, Mark M.; Dalal, Darshan; Tichnell, Crystal; James, Cynthia Anne; Tucker, April; Abraham, Theodore; Spevak, Philip J; Calkins, Hugh; Judge, Daniel P.

In: Human Mutation, Vol. 27, No. 11, 11.2006, p. 1157.

Research output: Contribution to journalArticle

Awad, MM, Dalal, D, Tichnell, C, James, CA, Tucker, A, Abraham, T, Spevak, PJ, Calkins, H & Judge, DP 2006, 'Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.', Human Mutation, vol. 27, no. 11, pp. 1157.
Awad, Mark M. ; Dalal, Darshan ; Tichnell, Crystal ; James, Cynthia Anne ; Tucker, April ; Abraham, Theodore ; Spevak, Philip J ; Calkins, Hugh ; Judge, Daniel P. / Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. In: Human Mutation. 2006 ; Vol. 27, No. 11. pp. 1157.
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