{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:32:50Z","timestamp":1791077570051,"version":"4.1.0"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"18","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,5,2]]},"abstract":"\n Congenital progressive hydronephrosis (\n cph<\/jats:italic>\n ) is a spontaneous recessive mutation that causes severe hydronephrosis and obstructive nephropathy in affected mice. The mutation has been mapped to the distal end of mouse chromosome 15, but the mutated gene has not been found. Here, we describe the identification of a single base pair change in\n aquaporin-2<\/jats:italic>\n (\n Aqp2<\/jats:italic>\n ) in\n cph<\/jats:italic>\n mutants through genetic linkage mapping. The C-T change led to the substitution of a Ser (S256) by a Leu in the cytoplasmic tail of the Aqp2 protein, preventing its phosphorylation at S256 and the subsequent accumulation of Aqp2 on the apical membrane of the collecting duct principal cells. The interference with normal trafficking of Aqp2 by this mutation resulted in a severe urine concentration defect.\n cph<\/jats:italic>\n homozygotes demonstrated polydipsia and produced a copious amount of hypotonic urine. The urine concentration defect could not be corrected by [deamino-Cys\n 1<\/jats:sup>\n ,\n d<\/jats:sc>\n -Arg\n 8<\/jats:sup>\n ]-vasopressin (DDAVP, a vasopressin analog), characteristic of nephrogenic diabetes insipidus. The nephrogenic diabetes insipidus symptoms and the absence of developmental defects in the pyeloureteral peristaltic machinery in the mutants before the onset of hydronephrosis suggest that the congenital obstructive nephropathy is most likely a result of the polyuria. This study has revealed the genetic basis for the classical\n cph<\/jats:italic>\n mutation and has provided direct genetic evidence that S256 in Aqp2 is indispensable for the apical accumulation, but not the general glycosylation or membrane association, of Aqp2.\n <\/jats:p>","DOI":"10.1073\/pnas.0602087103","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T00:05:46Z","timestamp":1146009946000},"page":"6952-6957","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":124,"title":["Congenital progressive hydronephrosis (\n cph<\/i>\n ) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylation and apical membrane accumulation"],"prefix":"10.1073","volume":"103","author":[{"given":"Bradley W.","family":"McDill","sequence":"first","affiliation":[{"name":"*Renal Division, Department of Internal Medicine, Department of Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Zhe","family":"Li","sequence":"additional","affiliation":[{"name":"*Renal Division, Department of Internal Medicine, Department of Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Kovach","sequence":"additional","affiliation":[{"name":"*Renal Division, Department of Internal Medicine, Department of Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[{"name":"Genome Sequencing Center, Washington University School of Medicine, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"*Renal Division, Department of Internal Medicine, Department of Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,5,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050756"},{"key":"e_1_3_3_2_2","unstructured":"M. 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