HNF1B alterations associated with congenital anomalies of the kidney and urinary tract
HNF1B alterations associated with congenital anomalies of the kidney and urinary tract
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DOI：
10.1007/s00467-010-1454-9
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发表时间：
2010-06-01
影响因子：
3
通讯作者：
Iijima, Kazumoto
中科院分区：
文献类型：
--
作者：
Nakayama, Makiko;Nozu, Kandai;Iijima, Kazumoto
肝细胞核因子1 β（HNF 1 β）异常已被确认为导致先天性肾脏和泌尿道异常（CAKUT），主要影响双侧肾脏畸形。为了进一步了解HNF 1 β相关表型的谱，我们对日本肾发育不良（n = 31）、单侧多囊性发育不良肾（MCDK; n = 14）和其他（n = 5）患者进行了HNF 1B基因突变和缺失分析。我们在50例患者中发现了5例（10%）HNF 1B改变。在3例单侧MCDK患者中发现HNF-1B基因完全缺失。其中2例患者显示对侧发育不全，而另1例患者显示对侧肾脏放射学正常，肾功能正常。拷贝数变异分析表明，1.4 Mb的微缺失涉及整个HNF 1B基因的断裂点在侧翼节段重复。我们还在双侧发育不良患者中发现了1个新的截短突变（1007 insC）和另一个错义突变（226 G> T）。HNF 1B改变导致单倍不足，影响CAKUT的多样性。肾功能正常的单侧MCDK患者的存在可能为这些仅患有单侧MCDK的大量人群的病因提供遗传学见解。包括HNF 1B在内的复发性微缺失可能对HNF 1B缺失的机制产生重大影响。
Hepatocyte nuclear factor 1 beta (HNF1 beta) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1 beta related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n = 31), unilateral multicystic dysplastic kidney (MCDK; n = 14) and others (n = 5). We identified HNF1B alterations in 5 out of 50 patients (10%). De novo heterozygous complete deletions of HNF1B were found in 3 patients with unilateral MCDK. Two of the patients showed contralateral hypodysplasia, whereas the other patient showed a radiologically normal contralateral kidney with normal renal function. Copy number variation analyses showed 1.4 Mb microdeletions involving the whole HNF1B gene with breakpoints in flanking segmental duplications. We also identified 1 novel truncated mutation (1007insC) and another missense mutation (226G > T) in patients with bilateral hypodysplasia. HNF1B alterations leading to haploinsufficiency affect a diverse spectrum of CAKUT. The existence of a patient with unilateral MCDK with normal renal function might provide genetic insight into the etiology of these substantial populations of only unilateral MCDK. The recurrent microdeletions encompassing HNF1B could have a significant impact on the mechanism of HNF1B deletions.