Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease
Mutation detection of PKD1 identifies a novel mutation common to three families with aneurysms and/or very-early-onset disease
复制标题
DOI：
10.1086/302657
复制
发表时间：
1999-12-01
影响因子：
9.8
通讯作者：
Germino, GG
中科院分区：
文献类型：
--
作者：
Watnick, T;Phakdeekitcharoen, B;Germino, GG
众所周知，常染色体显性多囊肾病的一些最严重的并发症，如颅内动脉瘤，在家族中聚集。然而，迄今为止还没有研究报告，试图将严重影响的谱系与特定基因型联系起来。事实上，直到最近，对大多数PKD1基因的突变检测几乎是不可能的，因为16号染色体上也存在几个高度同源的位点。在本报告中，我们描述了PKD1独有的外显子15中一个4 bp的片段。在这个位置设计正向和反向pkd1特异性引物，通过远程PCR扩增基因外显子11-21的区域。所描述的两个模板用于分析35个家系，因为它们包括颅内动脉瘤和/或非常早发性疾病的个体。我们发现了8个新的截断突变，2个在对照组中未发现的错义突变，以及几个信息多态性。许多多态性也存在于同源位点中，这支持了它们可能作为PKD1基因遗传变异性储存库的观点。令人惊讶的是，我们发现三个独立确定的家系在第15外显子有相同的2 bp缺失。这增加了特定基因型可能与更严重疾病相关的可能性。
It is known that several of the most severe complications of autosomal-dominant polycystic kidney disease, such as intracranial aneurysms, cluster in families. There have been no studies reported to date, however, that have attempted to correlate severely affected pedigrees with a particular genotype. Until recently, in fact, mutation detection for most of the PKD1 gene was virtually impossible because of the presence of several highly homologous loci also located on chromosome 16. In this report we describe a duster of 4 bp in exon 15 that are unique to PKD1. Forward and reverse PKD1-specific primers were designed in this location to amplify regions of the gene from exons 11-21 by use of long-range PCR, The two templates described were used to analyze 35 pedigrees selected for study because they included individuals with either intracranial aneurysms and/or very-early-onset disease. We identified eight novel truncating mutations, two missense mutations not found in a panel of controls, and several informative polymorphisms. Many of the polymorphisms were also present in the homologous loci, supporting the idea that they may serve as a reservoir for genetic variability in the PKD1 gene. Surprisingly, we found that three independently ascertained pedigrees had an identical 2-bp deletion in exon 15. This raises the possibility that particular genotypes may be associated with more-severe disease.