Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.
Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.
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DOI：
10.1002/humu.9461
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发表时间：
2006-11-01
期刊：
影响因子：
3.9
通讯作者：
Judge, Daniel P
中科院分区：
文献类型：
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作者：
Awad, Mark M;Dalal, Darshan;Judge, Daniel P
致心律失常性右室发育不良(ARVD)是一种遗传性疾病，导致右室肌细胞纤维脂肪替代，随之而来的室性心律失常。PKP2基因杂合性突变可导致显性ARVD，外显性降低。我们报告了第一例由PKP2突变引起的隐性ARVD。对一例典型的先证者进行候选基因分析，发现PKP2(c.[2484C>；T]+[2484C>；T])中存在一种新的纯合子突变，该突变被预测为翻译沉默(p.Gly828)。然而，对先证者的mRNA分析表明，该突变主要导致隐匿性剪接，外显子12有7个核苷酸缺失。随之而来的框架转换扰乱了PLAKAPRIN-2的最后54个氨基酸，并将开放阅读框架延长了145个核苷酸(48个氨基酸)到3‘非翻译区。单倍型分析表明没有远亲血缘关系。杂合子家族成员产生约60%的正确剪接的PKP2，并且没有ARVD的表现。进一步分析PKP2的mRNA序列，发现了另外两个选择性剪接的转录本。隐蔽或选择性剪接的可能性应该随着该基因中明显同义的核苷酸替换的鉴定而被考虑。
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.