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1.
Juliane L. Rocha Eitan Friedman Wolfanga Boson Ayrton Moreira Bonald Figueiredo Bernardo Liberman Luiz de Lacerda Romulo Sandrini Hans Graf Sonia Martins Marcia K. Puales Luiz De Marco 《Human mutation》1999,14(3):233-239
Nephrogenic diabetes insipidus (NDI) is associated with germline mutations in two genes: vasopressin receptor type 2 (V2(R)) in X‐linked NDI, and the water channel aquaporin‐2, in autosomal‐recessive disease. Genetic heterogeneity is further emphasized by reports of phenotypically abnormal individuals with normal structural genes. We analyzed both genes in five Brazilian families and the aquaporin‐2 gene in two Swedish families with clinical and laboratory diagnosis of NDI, by a combination of denaturing gradient gel electrophoresis (DGGE) and direct DNA sequencing. A novel polymorphism in the aquaporin‐2 gene (S167S), but no disease‐associated mutations in any tested individual from all seven families, was detected. In two Brazilian families, frameshift mutations were detected in the V2(R) gene: one leading to a premature stop after codon 36 and the other to a longer peptide (462 aa instead of the 373 aa wild‐type protein). In two other Brazilian families, probable disease‐associated missense mutations were detected: an alanine to proline at codon 163 (A163P) and an asparagine to aspartic acid at codon 85 (D85N). In one Brazilian family, both genes were structurally normal and the aquaporin‐2 gene was also normal in the two Swedish kindreds. This report further extends the mutational spectrum of NDI and suggests that there are other mutational or epigenetic events inactivating the two known genes or even novel genes that underlie NDI. Hum Mutat 14:233–239, 1999. © 1999 Wiley‐Liss, Inc. 相似文献
2.
Kamsteeg EJ Savelkoul PJ Hendriks G Konings IB Nivillac NM Lagendijk AK van der Sluijs P Deen PM 《Pflügers Archiv : European journal of physiology》2008,455(6):1041-1054
To stimulate renal water reabsorption, vasopressin induces phosphorylation of Aquaporin-2 (AQP2) water channels at S256 and
their redistribution from vesicles to the apical membrane, whereas vasopressin removal results in AQP2 ubiquitination at K270
and its internalization to multivesicular bodies (MVB). AQP2-E258K causes dominant nephrogenic diabetes insipidus (NDI), but
its subcellular location is unclear, and the molecular reason for its involvement in dominant NDI is unknown. To unravel these,
AQP2-E258K was studied in transfected polarized Madin–Darby canine kidney (MDCK) cells. In MDCK cells, AQP2-E258K mainly localized
to MVB/lysosomes (Lys). Upon coexpression, wild-type (wt) AQP2 and AQP2-E258K formed multimers, which also localized to MVB/Lys,
independent of forskolin stimulation. Orthophosphate labeling revealed that forskolin increased phosphorylation of wt-AQP2
and AQP2-E258K but not AQP2-S256A, indicating that the E258K mutation does not interfere with the AQP2 phosphorylation at
S256. In contrast to wt-AQP2 but consistent with the introduced protein kinase C (PKC) consensus site, AQP2-E258K was phosphorylated
by phorbol esters. Besides the 29-kDa band, however, an additional band of about 35 kDa was observed for AQP2-E258K only,
which represented AQP2-E258K uniquely monoubiquitinated at K228 only. Analysis of several mutants interfering with AQP2-E258K
phosphorylation, and/or ubiquitination, however, revealed that the MVB/lysosomal sorting of AQP2-E258K occurred independent
of its monoubiquitination or phosphorylation by PKC. Instead, our data reveal that the loss of the E258 in AQP2-E258K is fundamental
to its missorting to MVB/Lys and indicate that this amino acid has an important role in the proper structure formation of
the C-terminal tail of AQP2. 相似文献