Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease
Bilineal disease and trans-heterozygotes in autosomal dominant polycystic kidney disease
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DOI：
10.1086/318188
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发表时间：
2001-02-01
影响因子：
9.8
通讯作者：
St George-Hyslop, P
中科院分区：
文献类型：
--
作者：
Pei, Y;Paterson, AD;St George-Hyslop, P
在寻找常染色体显性遗传性多囊肾病（ADPKD）的第三个基因时，我们研究了一个大家族（NFL 10）的遗传遗传，该家族以前被排除在PKD 1位点和PKD 2位点的连锁之外。我们通过超声检查筛选了NFL 10家系的48名成员，并在PKD 1位点和PKD 2位点用信息标记对其进行基因分型。48名受评估的个体中有28名受ADPKD影响。检查这些人的单倍型表明，独立分离PKD 1和PKD 2突变的可能性双系疾病。使用单链构象分析，我们筛选并发现PKD 2突变（即，2152delA; L736X）。此外，当这些个体的疾病状态在连锁分析中被编码为“未知”时，我们还发现，在PKD 1基因座上的标记物，显著的LOD评分（即，>3.0）。这些发现强烈支持在其他15个受影响的家系成员中存在PKD 1突变，他们缺乏PKD 2突变。另外两个受影响的个体有涉及两个基因的反式杂合突变，他们的肾脏疾病比单独有突变的受影响个体更严重。这是第一个文件的双线疾病的ADPKD。在人类中，涉及PKD 1和PKD 2的反式杂合突变不一定是胚胎致死的。然而，与两种突变的存在相关的疾病似乎比与单独的任一突变相关的疾病更严重。在寻找难以捉摸的PKD 3位点时，需要认真考虑双系疾病作为混杂因素的存在。
In searching for a putative third gene for autosomal dominant polycystic kidney disease (ADPKD), we studied the genetic inheritance of a large family (NFL10) previously excluded from linkage to both the PKD1 locus and the PKD2 locus. We screened 48 members of the NFL10 pedigree, by ultrasonography, and genotyped them, with informative markers, at both the PKD1 locus and the PKD2 locus. Twenty-eight of 48 individuals assessed were affected with ADPKD. Inspection of the haplotypes of these individuals suggested the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations. Using single-stranded conformational analysis, we screened for and found a PKD2 mutation (i.e., 2152delA; L736X) in 12 affected pedigree members. Additionally, when the disease status of these individuals was coded as "unknown" in linkage analysis, we also found, with markers at the PKD1 locus, significant LOD scores (i.e., >3.0). These findings strongly support the presence of a PKD1 mutation in 15 other affected pedigree members, who lack the PKD2 mutation. Two additional affected individuals had trans-heterozygous mutations involving both genes, and they had renal disease that was more severe than that in affected individuals who had either mutation alone. This is the first documentation of bilineal disease in ADPKD. In humans, trans-heterozygous mutations involving both PKD1 and PKD2 are not necessarily embryonically lethal. However, the disease associated with the presence of both mutations appears to be more severe than the disease associated with either mutation alone. The presence of bilineal disease as a confounder needs to be considered seriously in the search for the elusive PKD3 locus.