Identification and properties of TRPV4 mutant channels present in polycystic kidney disease patients

Function Pub Date : 2024-06-13 DOI:10.1093/function/zqae031
Ana M. Hernández-Vega, Itzel Llorente, Raúl Sánchez-Hernández, Yayoi Segura, Teresa Tusié-Luna, Luis E Morales-Buenrostro, R. García-Villegas, León D Islas, Tamara Rosenbaum
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Abstract

Polycystic kidney disease (PKD), a disease characterized by enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. TRPV4, a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations.
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多囊肾患者体内 TRPV4 突变通道的鉴定和特性
多囊肾病(PKD)是一种以肾脏因囊性增生而增大为特征的疾病,是全球第四大终末期肾病病因。TRPV4是一种钙离子渗透性TRP通道,参与肾脏细胞的生理功能,由于TRPV4与另一种通道TRPP2(或PKD2)形成复合物,而TRPP2的功能失常与PKD有关,因此我们试图确定PKD患者是否表现出以前未知的TRPV4突变。在这里,我们报告了在确诊为 PKD 的患者中存在 TRPV4 基因突变,并确定这些突变会产生功能增益(GOF)。TRPV4 基因序列中的突变与多种神经病和骨骼发育不良有关,但与 PKD 无关,它们对通道功能的生物物理影响尚未阐明。我们发现并研究了一种新型 E6K 突变体以及之前已知的 S94L 和 A217S 突变体 TRVP4 通道的功能行为。A217S突变与混合神经病变和/或骨骼发育不良表型有关,但这些变体的PKD携带者并未被诊断出这些临床表现。TRPV4中某些突变的存在可能会通过GOF机制影响PKD的进展和严重程度。与没有 TRVP4 突变的患者相比,携带 TRVP4 突变的 PKD 患者需要透析或肾移植的可能性更大。
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