Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction
Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction
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DOI：
10.1016/j.ajhg.2019.03.023
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发表时间：
2019-05-02
影响因子：
9.8
通讯作者：
Hilger, Alina C.
中科院分区：
文献类型：
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作者：
Kolvenbach, Caroline M.;Dworschak, Gabriel C.;Hilger, Alina C.
先天性下尿路梗阻(Luto)是由膀胱流出道解剖阻塞或排尿功能障碍引起的。大约每10,000名孕妇中就有3名受到影响。虽然已经定义了几种功能性阻塞的单基因原因，但尚不清楚解剖阻塞引起的先天性黄体生成是否有单基因原因。在一个有四个患有尿路解剖阻塞的患者的家庭中，外显子组测序发现了BNC2中一个罕见的无意义变异(c.2557C>；T[p.Arg853*])，编码basonuclin 2，跟踪了三代人的Luto。对697名带有Luto基因的个体的BNC2进行重新测序，发现在三个不相关的家族中还有另外三个独立的错义变体。在人和小鼠胚胎发育过程中，在下尿路中检测到了Basonuclin 2。在斑马鱼胚胎中，BNC2表达于前肾管和泄殖腔，这是哺乳动物下尿路的类似物。BNC2基因在斑马鱼体内的实验敲除导致前肾出口阻塞和泄殖腔扩张，表现为人类先天性黄体。总之，这些结果支持这样的结论，即BNC2的变异与黄体病因学密切相关，这是解剖阻塞的结果。
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853*]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Resequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.