Badenas C, Torra R, Pérez-Oller L, Mallolas J, Talbot-Wright R, Torregrosa V, Darnell A
Department of Nephrology, Hospital Clinic, Institut d'Investigacions BiomMèdiques August Pi i Sunyer, University of Barcelona, Spain.
Eur J Hum Genet. 2000 Jul;8(7):487-92. doi: 10.1038/sj.ejhg.5200484.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.
常染色体显性多囊肾病（ADPKD）是人类最常见的遗传病之一，在白种人群中发病率为1:1000。它由PKD1或PKD2基因突变引起。最近，关于囊肿起始的突变机制有一些有争议的数据报道：基因分析表明，第二次体细胞突变可能导致囊肿形成（表现为微卫星杂合性缺失，即LOH，以及点突变），但免疫组化研究显示，在一些囊肿中多囊蛋白有很强的免疫反应性。为了进一步明确这一问题，我们分析了来自7名不同患者的211个囊肿的杂合性缺失情况，检测到PKD1的杂合性缺失率为13.3%。这种缺失是PKD1特有的，因为研究其他染色体区域时未检测到杂合性缺失。只要进行了连锁分析，就已证明丢失的等位基因对应野生型。由于研究的囊肿数量众多，我们的数据支持了先前关于ADPKD的二次打击理论的结果。ADPKD可能通过隐性细胞机制发生。囊肿发生的概率将取决于第二个等位基因突变的概率。ADPKD中报道的相同突变的不同表型表达可能是由于每个个体中第二个等位基因失活的不同倾向。
