Nephrolithiasis or renal stone disease is an increasingly common problem, and its relatively high recurrence rate demands better treatment options. The majority of patients with nephrolithiasis have stones that contain calcium (Ca²⁺), which develop upon “supersaturation” of the urine with insoluble Ca²⁺ salts; hence processes that influence the delivery and renal handling of Ca²⁺ may influence stone formation. Idiopathic hypercalciuria is indeed frequently observed in patients with kidney stones that contain Ca²⁺. Genetic screens of nephrolithiasis determinants have identified an increasing number of gene candidates, most of which are involved in renal Ca²⁺ handling. This review provides an outline of the current knowledge regarding genetics of nephrolithiasis and will mainly focus on the epithelial Ca²⁺ channel transient receptor potential vanilloid 5 (TRPV5), an important player in Ca²⁺ homeostasis. Being a member of the TRP family of ion channels, TRPV5 is currently part of a revolution in structural biology. Recent technological breakthroughs in the cryo-electron microscopy field, combined with improvements in biochemical sample preparation, have resulted in high-resolution 3-dimensional structural models of integral membrane proteins, including TRPV5. These models currently are being used to explore the proteins’ structure-function relationship, elucidate the molecular mechanisms of channel regulation, and study the putative effects of disease variants. Combined with other multidisciplinary approaches, this approach may open an avenue toward better understanding of the pathophysiological mechanisms involved in hypercalciuria and stone formation, and ultimately it may facilitate prevention of stone recurrence through the development of effective drugs.

肾结石或肾结石病是一个日益普遍的问题，其较高的复发率需要更好的治疗选择。大多数肾结石病患者的结石中都含有钙（Ca ²⁺），这些钙是在尿液中不溶性Ca ²⁺盐“过饱和”时形成的。因此，影响Ca ²⁺传递和肾脏处理的过程可能会影响结石形成。的确，在含有Ca ^2+的肾结石患者中经常观察到特发性高钙尿症。肾结石病决定因素的遗传筛选已鉴定出越来越多的基因候选物，其中大多数与肾脏Ca ^2+有关处理。这篇综述概述了有关肾结石病遗传学的最新知识，并将主要关注上皮Ca ²⁺通道瞬态受体电位香草酸5（TRPV5），Ca ²⁺的重要参与者稳态。作为TRP离子通道家族的成员，TRPV5当前是结构生物学革命的一部分。冷冻电子显微镜领域的最新技术突破，加上生化样品制备的改进，已经形成了完整的膜蛋白（包括TRPV5）的高分辨率3维结构模型。这些模型目前用于探索蛋白质的结构-功能关系，阐明通道调节的分子机制，并研究疾病变体的推定作用。结合其他多学科方法，该方法可以为更好地了解高钙尿症和结石形成的病理生理机制开辟一条道路，