Prune belly syndrome (PBS), also known as Eagle-Barret syndrome, is a rare, multi-system congenital myopathy primarily affecting males. Phenotypically, PBS cases manifest three cardinal pathological features: urinary tract dilation with poorly contractile smooth muscle, wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, and intra-abdominal undescended testes. Genetically, PBS is poorly understood. After performing whole exome sequencing in PBS patients, we identify one compound heterozygous variant in the PIEZO1 gene. PIEZO1 is a cation-selective channel activated by various mechanical forces and widely expressed throughout the lower urinary tract. Here we conduct an extensive functional analysis of the PIEZO1 PBS variants that reveal loss-of-function characteristics in the pressure-induced normalized open probability (NPo) of the channel, while no change is observed in single-channel currents. Furthermore, Yoda1, a PIEZO1 activator, can rescue the NPo defect of the PBS mutant channels. Thus, PIEZO1 mutations may be causal for PBS and the in vitro cellular pathophysiological phenotype could be rescued by the small molecule, Yoda1. Activation of PIEZO1 might provide a promising means of treating PBS and other related bladder dysfunctional states.

Prune Belly 综合征 （PBS），也称为 Eagle-Barret 综合征，是一种罕见的多系统先天性肌病，主要影响男性。从表型上看，PBS 病例表现为 3 个主要病理特征：尿路扩张伴平滑肌收缩不良、腹壁皱纹松弛伴骨骼肌缺陷和腹腔内未降睾丸。从遗传学上讲，人们对 PBS 知之甚少。在 PBS 患者中进行全外显子组测序后，我们在 PIEZO1 基因中鉴定出一个复合杂合变异。PIEZO1 是一种由各种机械力激活的阳离子选择性通道，在整个下尿路广泛表达。在这里，我们对 PIEZO1 PBS 变体进行了广泛的功能分析，揭示了通道压力诱导的归一化开路概率 （NPo） 的功能丧失特性，而在单通道电流中没有观察到变化。此外，PIEZO1 激活剂 Yoda1 可以挽救 PBS 突变通道的 NPo 缺陷。因此，PIEZO1 突变可能是 PBS 的因果关系，并且体外细胞病理生理表型可以被小分子 Yoda1 挽救。PIEZO1 的激活可能为治疗 PBS 和其他相关的膀胱功能障碍状态提供了一种有前途的方法。