Identification and Properties of TRPV4 Mutant Channels Present in Polycystic Kidney Disease Patients
Por:
Hernández-Vega, AM, Llorente, I, Sánchez-Hernández, R, Segura, Y, Tusié-Luna, T, Morales-Buenrostro, LE, García-Villegas, R, Islas, LD, Rosenbaum, T
Publicada:
10 sep 2024
Resumen:
Polycystic kidney disease (PKD), a disease characterized by the enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. Transient receptor potential Vanilloid 4 (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.
Graphical Abstract Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease.
Filiaciones:
Hernández-Vega, AM:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencia Cognit, Ciudad De Mexico 04510, Mexico
Llorente, I:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencia Cognit, Ciudad De Mexico 04510, Mexico
Sánchez-Hernández, R:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencia Cognit, Ciudad De Mexico 04510, Mexico
Segura, Y:
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Unidad Biol Mol & Med Genom, Ciudad De Mexico 14080, Mexico
Tusié-Luna, T:
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Unidad Biol Mol & Med Genom, Ciudad De Mexico 14080, Mexico
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Ciudad de Mexico 04510, Mexico
Morales-Buenrostro, LE:
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nefrol & Metab Mineral, Ciudad De Mexico 14080, Mexico
García-Villegas, R:
Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Ave Inst Politecn Nacl 2508, Ciudad De Mexico 07360, Mexico
Islas, LD:
Univ Nacl Autonoma Mexico, Fac Med, Dept Fisiol, Ciudad De Mexico 04510, Mexico
Rosenbaum, T:
Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Neurociencia Cognit, Ciudad De Mexico 04510, Mexico
Green Published, gold, All Open Access; Gold Open Access
|