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.
摘要：
多囊肾病(PKD),一种以通过囊性生长使肾脏增大为特征的疾病是全球终末期肾脏疾病的第四大原因。TRPV4，一种钙渗透性TRP，通道参与肾细胞生理学，并且由于TRPV4与另一个通道形成复合物，该通道的功能障碍与PKD有关，TRPP2（或PKD2），我们试图确定PKD患者，在TRPV4中表现出以前未知的突变。这里,我们报告了TRPV4基因突变在诊断为PKD的患者中的存在,并确定它们产生了功能获得(GOF).TRPV4基因的序列突变与广泛的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。我们鉴定并检查了新型E6K突变体和先前已知的S94L和A217S突变体TRVP4通道的功能行为。A217S突变与混合性神经病和/或骨骼发育不良表型相关，然而,这些变异的PKD携带者没有被诊断为这些报告的临床表现.TRPV4中某些突变的存在可能通过GOF机制影响PKD的进展和严重程度。与没有这些突变的患者相比，携带TRVP4突变的PKD患者更可能需要透析或肾移植。
