A missense mutation in PKD1 attenuates the severity of renal disease.
A missense mutation in PKD1 attenuates the severity of renal disease.
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DOI：
10.1038/ki.2011.370
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发表时间：
2012-02
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
PKD 1和PKD 2的突变导致了大多数常染色体显性多囊肾病（ADPKD）病例。与PKD 2相比，PKD 1患者通常有更严重的肾脏疾病。在这里，我们报告了一个独特的多代家庭的后续研究与双线ADPKD（NFL 10），其中PKD 1疾病单倍型和PKD 2（L736 X）突变共分离与18和14个受影响的个人，分别。在我们更新的NFL 10基因型-表型分析中，我们发现PKD 1受影响的个体具有与PKD 2受影响的个体相似的均匀轻度肾脏疾病。通过对PKD 1的所有外显子和剪接点进行测序，我们从PKD 1受影响的个体中鉴定出两个错义突变（Y 528 C和R1942 H）。尽管预测这两种变体都对突变蛋白有损害，但只有Y 528 C与NFL 10中所有PKD 1受影响的个体共分离。为了进一步确定Y 528 C的致病性，我们在表达PKD 1野生型和突变型的稳定MDCK细胞系中进行了体外研究。我们发现表达Y 528 C变异体的MDCK细胞系在培养中形成包囊，并表现出生长和凋亡速率增加。综上所述，我们的数据表明，Y 528 C的功能作为一个亚型PKD 1等位基因。这些发现对ADPKD的致病机制和分子诊断具有重要意义。
Mutations of PKD1 and PKD2 account for most cases of autosomal dominant polycystic kidney disease (ADPKD). Compared to PKD2, patients with PKD1 typically have more severe renal disease. Here, we report a follow-up study of a unique multi-generation family with bilineal ADPKD (NFL10) in which a PKD1 disease haplotype and a PKD2 (L736X) mutation co-segregated with 18 and 14 affected individuals, respectively. In our updated genotype-phenotype analysis of NFL10, we found that PKD1-affected individuals had uniformly mild renal disease similar to PKD2-affected individuals. By sequencing all the exons and splice junctions of PKD1, we identified two missense mutations (Y528C and R1942H) from a PKD1-affected individual. Although both variants were predicted to be damaging to the mutant protein, only Y528C co-segregated with all the PKD1-affected individuals in NFL10. To further establish the pathogenicity of Y528C, we performed in-vitro studies in stable MDCK cell lines expressing wild-type and mutant forms of PKD1. We found that MDCK cell lines expressing the Y528C variant formed cysts in culture and demonstrated increased rates of growth and apoptosis. Taken together, our data suggest that Y528C functions as a hypomorphic PKD1 allele. These findings have important implications for pathogenic mechanisms and molecular diagnostics of ADPKD.
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影响因子：
9.8
作者：
Pei, Y;Paterson, AD;St George-Hyslop, P
通讯作者：
St George-Hyslop, P
DOI：
10.1097/01.asn.0000013300.11876.37
发表时间：
2002-05-01
影响因子：
13.6
作者：
Rossetti, S;Burton, S;Harris, PC
通讯作者：
Harris, PC
影响因子：
19.6
作者：
Rossetti, S;Chauveau, D;Harris, PC
通讯作者：
Harris, PC
影响因子：
13.6
作者：
Vujic, Mihailo;Heyer, Christina M.;Harris, Peter C.
通讯作者：
Harris, Peter C.
影响因子：
13.6
作者：
Phakdeekitcharoen, B;Watnick, TJ;Germino, GG
通讯作者：
Germino, GG