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  • Title: Effects of missense mutations on rat aquaporin-2 in LLC-PK1 porcine kidney cells.
    Author: Yamauchi K, Fushimi K, Yamashita Y, Shinbo I, Sasaki S, Marumo F.
    Journal: Kidney Int; 1999 Jul; 56(1):164-71. PubMed ID: 10411689.
    Abstract:
    BACKGROUND: Mutations in the aquaporin-2 (AQP2) gene have been found in families with nephrogenic diabetes insipidus (NDI), but the pathophysiological mechanisms of how mutant AQP2 causes the disease are still not clear. METHODS: Wild-type (WT) AQP2 and four mutants-T126M, A147T, R187C, and S216P-were transiently expressed in LLC-PK1 cells. The osmotic water permeability of LLC-PK1 cells expressing AQP2 mutants was determined by stopped-flow light-scattering microphotometry. Cell surface expression, subcellular localization, and effects of vasopressin stimulation were examined by surface biotin labeling and confocal immunohistochemistry. RESULTS: The osmotic water permeability (Pf) of cells expressing WT increased significantly after vasopressin treatment, whereas the Pf of cells expressing T126M A147T, R187C, and S216P was not significantly different from that of the control even after vasopressin stimulation. Confocal immunohistochemistry demonstrated distribution of WT and A147T in early/recycling endosomal compartments and vasopressin-responsive translocation and surface expression. In contrast, stainings of T126M, R187C, and S216P were similar to that of Grp78, indicating that these mutants were misassembled and retarded in the endoplasmic reticulum. CONCLUSION: Our results indicated that the intracellular distribution and vasopressin-regulated trafficking of A147T is intact, in contrast to the other three mutants, of which both were impaired. Thus, it is conceivable that the disruption of the AQP2 channel function accounts for the pathogenesis of A147T NDI, whereas trafficking defects account for that of the other types, suggesting that the pathophysiology of AQP2-related NDI is heterogeneous.
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