Ostrowska Dahlgren Bozena, Allen Marie, Lindström Anne-Cristine, Bjerke Mia, Blomström-Lundqvist Carina
Department of Cardiology, Uppsala University, Uppsala, Sweden.
J Interv Card Electrophysiol. 2012 Jun;34(1):11-8. doi: 10.1007/s10840-011-9643-4. Epub 2011 Dec 15.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of muscular fibers predominantly in the right ventricle and with ventricular arrhythmias as the main clinical manifestation. Mutations in several components of the desmosome genes have been identified and mutations of the plakophilin-2 (PKP-2) gene are a common cause of ARVC. The aim of this study is to investigate the correlation between genotype and phenotype in a family with a novel PKP-2 variant.
This study describes the clinical findings and genetic analysis in a family with ARVC. A part of the family has been followed clinically long term for up to 27 years. Two not previously reported PKP-2 variants (L506P and T526A) have been identified in this family. Even though all members of this family share the novel variant L506P, the clinical features, i.e., their phenotypes are different. The L506P variant is located in exon 7 and affects a highly conserved residue. The same amino acid, leucine, is present in all species evaluated, indicating a functional importance and the variant is predicted to be damaging. The novel L506P variant in the PKP-2 gene is thus a possible pathogenic alteration in the described family with ARVC. In contrast, the T526A variant is weakly conserved and predicted to be tolerated.
While many of the reported ARVC mutations are truncating mutations, the possibly damaging variant found in this family, is a missense alteration affecting a highly conserved residue 506 located in exon 7.
致心律失常性右室心肌病（ARVC）的特征是主要在右心室出现肌纤维的纤维脂肪替代，并以室性心律失常为主要临床表现。已确定桥粒基因的几个组分存在突变，而盘状球蛋白2（PKP - 2）基因的突变是ARVC的常见病因。本研究的目的是调查一个具有新型PKP - 2变异体的家系中基因型与表型之间的相关性。
本研究描述了一个ARVC家系的临床发现和基因分析。该家系的一部分成员已接受长达27年的长期临床随访。在这个家系中鉴定出两个先前未报道的PKP - 2变异体（L506P和T526A）。尽管这个家系的所有成员都携带新型变异体L506P，但他们的临床特征，即表型却有所不同。L506P变异体位于第7外显子，影响一个高度保守的残基。在所有评估的物种中都存在相同的氨基酸亮氨酸，这表明其具有功能重要性，并且该变异体预计具有损害性。因此，PKP - 2基因中的新型L506P变异体可能是所描述的这个ARVC家系中的致病改变。相比之下，T526A变异体保守性较弱，预计可被耐受。
虽然许多已报道的ARVC突变是截短突变，但在这个家系中发现的可能具有损害性的变异体是一个错义改变，影响位于第7外显子的高度保守残基506。
