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Molecular and cellular defects in nephrogenic diabetes insipidus
The identification of the different molecular causes of congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by renal insensitivity to the antidiuretic effect of arginine vasopressin, has been of indispensable importance for understanding the cellular processes involved in diure...
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Published in: | Pediatric nephrology (Berlin, West) West), 2001-12, Vol.16 (12), p.1146-1152 |
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description | The identification of the different molecular causes of congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by renal insensitivity to the antidiuretic effect of arginine vasopressin, has been of indispensable importance for understanding the cellular processes involved in diuresis and antidiuresis. In most cases, NDI is X-linked and caused by mutations in the vasopressin type-2 receptor (V2R) gene. Mutations in the aquaporin-2 (AQP2) water channel gene are responsible for the autosomal recessive and rare dominant forms of NDI. By in vitro expression, it has been shown that the majority of V2R mutants and all AQP2 mutants found in recessive NDI are misfolded and retained within the endoplasmic reticulum (ER). Functional analysis of one of the mutations identified in dominant NDI showed that this mutant is properly folded and transported out of the ER, but is retained in the Golgi region. In addition, this mutant, in contrast to mutants found in recessive NDI, is able to heterotetramerize with wild-type AQP2. The resulting complex is hindered in its transport to the membrane, a finding that explains the dominant-negative effect of this mutation. Several new methodologies focused on the molecular defects causing NDI are presently being investigated in vitro and might eventually develop into useful therapeutic strategies. |
doi_str_mv | 10.1007/s004670100051 |
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Functional analysis of one of the mutations identified in dominant NDI showed that this mutant is properly folded and transported out of the ER, but is retained in the Golgi region. In addition, this mutant, in contrast to mutants found in recessive NDI, is able to heterotetramerize with wild-type AQP2. The resulting complex is hindered in its transport to the membrane, a finding that explains the dominant-negative effect of this mutation. 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Apud cells (diseases) ; Endocrinopathies ; Genes, Dominant ; Genes, Recessive ; Genetic counseling ; Genetic Linkage ; Genotype ; Humans ; Kidney Tubules, Collecting - physiopathology ; Kinases ; Medical sciences ; Mutation ; Permeability ; Phenotype ; Physiology ; Plasma ; Proteins ; Vasopressins - physiology ; X Chromosome</subject><ispartof>Pediatric nephrology (Berlin, West), 2001-12, Vol.16 (12), p.1146-1152</ispartof><rights>2002 INIST-CNRS</rights><rights>IPNA - International Pediatric Nephrology Association New York, USA 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-51b3497c80c62b4a155f6aa3e3fe5698de46db9d9c3b87efc5437f129637cf133</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14143494$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11793119$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KNOERS, Nine V. A. M</creatorcontrib><creatorcontrib>DEEN, Peter M. T</creatorcontrib><title>Molecular and cellular defects in nephrogenic diabetes insipidus</title><title>Pediatric nephrology (Berlin, West)</title><addtitle>Pediatr Nephrol</addtitle><description>The identification of the different molecular causes of congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by renal insensitivity to the antidiuretic effect of arginine vasopressin, has been of indispensable importance for understanding the cellular processes involved in diuresis and antidiuresis. In most cases, NDI is X-linked and caused by mutations in the vasopressin type-2 receptor (V2R) gene. Mutations in the aquaporin-2 (AQP2) water channel gene are responsible for the autosomal recessive and rare dominant forms of NDI. By in vitro expression, it has been shown that the majority of V2R mutants and all AQP2 mutants found in recessive NDI are misfolded and retained within the endoplasmic reticulum (ER). Functional analysis of one of the mutations identified in dominant NDI showed that this mutant is properly folded and transported out of the ER, but is retained in the Golgi region. In addition, this mutant, in contrast to mutants found in recessive NDI, is able to heterotetramerize with wild-type AQP2. The resulting complex is hindered in its transport to the membrane, a finding that explains the dominant-negative effect of this mutation. Several new methodologies focused on the molecular defects causing NDI are presently being investigated in vitro and might eventually develop into useful therapeutic strategies.</description><subject>Aquaporins</subject><subject>Associated diseases and complications</subject><subject>Biological and medical sciences</subject><subject>Congenital diseases</subject><subject>Diabetes</subject><subject>Diabetes Insipidus, Nephrogenic - genetics</subject><subject>Diabetes Insipidus, Nephrogenic - pathology</subject><subject>Diabetes Insipidus, Nephrogenic - physiopathology</subject><subject>Diabetes Insipidus, Nephrogenic - therapy</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diagnosis, Differential</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Genes, Dominant</subject><subject>Genes, Recessive</subject><subject>Genetic counseling</subject><subject>Genetic Linkage</subject><subject>Genotype</subject><subject>Humans</subject><subject>Kidney Tubules, Collecting - physiopathology</subject><subject>Kinases</subject><subject>Medical sciences</subject><subject>Mutation</subject><subject>Permeability</subject><subject>Phenotype</subject><subject>Physiology</subject><subject>Plasma</subject><subject>Proteins</subject><subject>Vasopressins - physiology</subject><subject>X Chromosome</subject><issn>0931-041X</issn><issn>1432-198X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNpd0U1LwzAYB_AgipvTo1cpgt6qSfN-U4ZvMPGisFtJkyfa0bUzaQ9-ezNXEM0lbz8envyD0CnBVwRjeR0xZkLitMac7KEpYbTIiVbLfTTFmpIcM7KcoKMYV4korsQhmhAi0xXRU3Tz3DVgh8aEzLQus9A0PxsHHmwfs7rNWth8hO4d2tpmrjYV9LA9j_WmdkM8RgfeNBFOxnmG3u7vXueP-eLl4Wl-u8gtVbzPOako09IqbEVRMUM498IYCtQDF1o5YMJV2mlLKyXBW86o9KTQgkrrCaUzdLmruwnd5wCxL9d13LZrWuiGWMqCaiaZSPD8H1x1Q2hTb2WRhmIyvX2G8h2yoYsxgC83oV6b8FUSXG5zLf_kmvzZWHSo1uB-9RhkAhcjMNGaxgfT2jr-Opb-hWlGvwENbH6R</recordid><startdate>20011201</startdate><enddate>20011201</enddate><creator>KNOERS, Nine V. 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Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Genes, Dominant</topic><topic>Genes, Recessive</topic><topic>Genetic counseling</topic><topic>Genetic Linkage</topic><topic>Genotype</topic><topic>Humans</topic><topic>Kidney Tubules, Collecting - physiopathology</topic><topic>Kinases</topic><topic>Medical sciences</topic><topic>Mutation</topic><topic>Permeability</topic><topic>Phenotype</topic><topic>Physiology</topic><topic>Plasma</topic><topic>Proteins</topic><topic>Vasopressins - physiology</topic><topic>X Chromosome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KNOERS, Nine V. A. M</creatorcontrib><creatorcontrib>DEEN, Peter M. 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A. M</au><au>DEEN, Peter M. T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular and cellular defects in nephrogenic diabetes insipidus</atitle><jtitle>Pediatric nephrology (Berlin, West)</jtitle><addtitle>Pediatr Nephrol</addtitle><date>2001-12-01</date><risdate>2001</risdate><volume>16</volume><issue>12</issue><spage>1146</spage><epage>1152</epage><pages>1146-1152</pages><issn>0931-041X</issn><eissn>1432-198X</eissn><coden>PENED3</coden><abstract>The identification of the different molecular causes of congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by renal insensitivity to the antidiuretic effect of arginine vasopressin, has been of indispensable importance for understanding the cellular processes involved in diuresis and antidiuresis. In most cases, NDI is X-linked and caused by mutations in the vasopressin type-2 receptor (V2R) gene. Mutations in the aquaporin-2 (AQP2) water channel gene are responsible for the autosomal recessive and rare dominant forms of NDI. By in vitro expression, it has been shown that the majority of V2R mutants and all AQP2 mutants found in recessive NDI are misfolded and retained within the endoplasmic reticulum (ER). Functional analysis of one of the mutations identified in dominant NDI showed that this mutant is properly folded and transported out of the ER, but is retained in the Golgi region. In addition, this mutant, in contrast to mutants found in recessive NDI, is able to heterotetramerize with wild-type AQP2. The resulting complex is hindered in its transport to the membrane, a finding that explains the dominant-negative effect of this mutation. Several new methodologies focused on the molecular defects causing NDI are presently being investigated in vitro and might eventually develop into useful therapeutic strategies.</abstract><cop>Heidelberg</cop><pub>Springer</pub><pmid>11793119</pmid><doi>10.1007/s004670100051</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Aquaporins Associated diseases and complications Biological and medical sciences Congenital diseases Diabetes Diabetes Insipidus, Nephrogenic - genetics Diabetes Insipidus, Nephrogenic - pathology Diabetes Insipidus, Nephrogenic - physiopathology Diabetes Insipidus, Nephrogenic - therapy Diabetes. Impaired glucose tolerance Diagnosis, Differential Endocrine pancreas. Apud cells (diseases) Endocrinopathies Genes, Dominant Genes, Recessive Genetic counseling Genetic Linkage Genotype Humans Kidney Tubules, Collecting - physiopathology Kinases Medical sciences Mutation Permeability Phenotype Physiology Plasma Proteins Vasopressins - physiology X Chromosome |
title | Molecular and cellular defects in nephrogenic diabetes insipidus |
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