Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life, and in utero obstruction to urine flow is a frequent cause of secondary upper urinary tract malformations. Here, using whole-exome sequencing, we identified three different biallelic mutations in CHRNA3, which encodes the α3 subunit of the nicotinic acetylcholine receptor, in five affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes. Functional studies in vitro demonstrated that the mutant nicotinic acetylcholine receptors were unable to generate current following stimulation with acetylcholine. Moreover, the truncating mutations p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. Although the importance of acetylcholine signaling in normal bladder function has been recognized, we demonstrate for the first time that mutations in CHRNA3 can cause bladder dysfunction, urinary tract malformations, and dysautonomia. These data point to a pathophysiologic sequence by which monogenic mutations in genes that regulate bladder innervation may secondarily cause CAKUT.

中文翻译：

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CAKUT和乙酰胆碱受体突变引起的自主神经功能障碍。

先天性肾脏和尿路异常（CAKUT）是生命的前三十年中慢性肾脏疾病的最常见原因，子宫内尿流阻塞是继发性上尿路畸形的常见原因。在这里，我们使用全外显子组测序，在三个功能相关的下尿路梗阻和继发性CAKUT的三个不相关家庭的五个受影响的个体中，确定了CHRNA3中的三个不同的双等位基因突变，该突变编码烟碱样乙酰胆碱受体的α3亚基。来自两个家庭的四个人还有其他的自主神经功能障碍，包括瞳孔光反射受损。体外功能研究表明，突变的烟碱型乙酰胆碱受体在乙酰胆碱刺激后无法产生电流。而且，p.Thr337Asnfs * 81和p.Ser340 *的截短突变导致CHRNA3的质膜定位受损。尽管已认识到乙酰胆碱信号在正常膀胱功能中的重要性，但我们首次证明了CHRNA3的突变可引起膀胱功能障碍，尿道畸形和自主神经功能减退。这些数据指出了病理生理序列，通过该序列，调节膀胱神经支配的基因中的单基因突变可继而引起CAKUT。