{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T23:21:47Z","timestamp":1763767307448,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","award":["Sidra Medicine #SDR400038"],"award-info":[{"award-number":["Sidra Medicine #SDR400038"]}],"id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal unresponsiveness to the hormone vasopressin, leading to excretion of large volumes of diluted urine. Mutations in the arginine vasopressin receptor-2 (AVPR2) gene cause congenital NDI and have an X-linked recessive inheritance. The disorder affects almost exclusively male family members, but female carriers occasionally present partial phenotypes due to skewed inactivation of the X-chromosome. Here, we report a rare case of a woman affected with X-linked recessive NDI, presenting an average urinary output of 12 L\/day. Clinical and biochemical studies showed incomplete responses to water deprivation and vasopressin stimulation tests. Genetic analyses revealed a novel heterozygous missense mutation (c.493G &gt; C, p.Ala165Pro) in the AVPR2 gene. Using a combination of in-silico protein modeling with human cellular models and molecular phenotyping, we provide functional evidence for phenotypic effects. The mutation destabilizes the helical structure of the AVPR2 transmembrane domains and disrupts its plasma membrane localization and downstream intracellular signaling pathways upon activation with its agonist vasopressin. These defects lead to deficient aquaporin 2 (AQP2) membrane translocation, explaining the inability to concentrate urine in this patient.<\/jats:p>","DOI":"10.3390\/jpm12010118","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T08:20:42Z","timestamp":1642407642000},"page":"118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clinical, Genetic and Functional Characterization of a Novel AVPR2 Missense Mutation in a Woman with X-Linked Recessive Nephrogenic Diabetes Insipidus"],"prefix":"10.3390","volume":"12","author":[{"given":"Senthil","family":"Selvaraj","sequence":"first","affiliation":[{"name":"Department of Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}]},{"given":"D\u00edrcea","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universit\u00e1rio de Coimbra, 3000-075 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5096-4612","authenticated-orcid":false,"given":"Navaneethakrishnan","family":"Krishnamoorthy","sequence":"additional","affiliation":[{"name":"Department of Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-1276","authenticated-orcid":false,"given":"Khalid A.","family":"Fakhro","sequence":"additional","affiliation":[{"name":"Department of Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medical College, Doha P.O. Box 24144, Qatar"},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 24144, Qatar"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-0396","authenticated-orcid":false,"given":"Lu\u00eds R.","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Department of Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 24144, Qatar"},{"name":"Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 19104, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-8900","authenticated-orcid":false,"given":"Manuel C.","family":"Lemos","sequence":"additional","affiliation":[{"name":"CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000493233","article-title":"Physiology and Pathophysiology of Water Homeostasis","volume":"52","author":"Berl","year":"2019","journal-title":"Front. Horm. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/s41572-019-0103-2","article-title":"Diabetes insipidus","volume":"5","author":"Bichet","year":"2019","journal-title":"Nat. Rev. Dis. 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