Novel Mutations in Aquaporin-2 Gene in Female Siblings with Nephrogenic Diabetes Insipidus: Evidence of Disrupted Water Channel Function

1998 ◽  
Vol 83 (9) ◽  
pp. 3205-3209 ◽  
Author(s):  
K. Goji
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Channel ◽  
Novel Mutations ◽  
Channel Function ◽  
Aquaporin 2

scholarly journals Novel Mutations in Aquaporin-2 Gene in Female Siblings with Nephrogenic Diabetes Insipidus: Evidence of Disrupted Water Channel Function1

1998 ◽  
Vol 83 (9) ◽  
pp. 3205-3209
Author(s):  
Katsumi Goji ◽  
Michio Kuwahara ◽  
Yong Gu ◽  
Masafumi Matsuo ◽  
Fumiaki Marumo ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Channel ◽  
Novel Mutations ◽  
Aquaporin 2

scholarly journals Two Novel Mutations in the Aquaporin 2 Gene in a Girl with Congenital Nephrogenic Diabetes Insipidus

2005 ◽  
Vol 20 (6) ◽  
pp. 1076 ◽  
Author(s):  
Hae Il Cheong ◽  
Su Jin Cho ◽  
Shou Huan Zheng ◽  
Hee Yeon Cho ◽  
Il Soo Ha ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Novel Mutations ◽  
Aquaporin 2 ◽  
Congenital Nephrogenic Diabetes Insipidus

scholarly journals Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus

2003 ◽  
Vol 163 (5) ◽  
pp. 1099-1109 ◽  
Author(s):  
Erik-Jan Kamsteeg ◽  
Daniel G. Bichet ◽  
Irene B.M. Konings ◽  
Hubert Nivet ◽  
Michelle Lonergan ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Water Conservation ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Channel ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Aquaporin 2 ◽  
Frame Shift ◽  
Polarized Delivery ◽  
Mutant Forms

Vasopressin regulates body water conservation by redistributing aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical surface of renal collecting ducts, resulting in water reabsorption from urine. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine. Here, we report a frame-shift mutation in AQP2 causing dominant NDI. This AQP2 mutant is a functional water channel when expressed in Xenopus oocytes. However, expressed in polarized renal cells, it is misrouted to the basolateral instead of apical plasma membrane. Additionally, this mutant forms heterotetramers with wild-type AQP2 and redirects this complex to the basolateral surface. The frame shift induces a change in the COOH terminus of AQP2, creating both a leucine- and a tyrosine-based motif, which cause the reversed sorting of AQP2. Our data reveal a novel cellular phenotype in dominant NDI and show that dominance of basolateral sorting motifs in a mutant subunit can be the molecular basis for disease.

scholarly journals Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5803-5810 ◽  
Author(s):  
Hidetaka Suga ◽  
Hiroshi Nagasaki ◽  
Taka-aki Kondo ◽  
Yoshiki Okajima ◽  
Chizuko Suzuki ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Sendai Virus ◽  
Collecting Duct ◽  
Water Channel ◽  
Vector System ◽  
Aquaporin 2 ◽  
Chronic Disorder ◽  
Life Threatening ◽  
Aqp2 Gene

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/ΔF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/ΔF vector carrying a human AQP2 gene (AQP2-SeV/ΔF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

scholarly journals Molecular Characterization of an Aquaporin−2 Mutation Causing Nephrogenic Diabetes Insipidus

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Li ◽  
Bichao Lu ◽  
Jia Yang ◽  
Chao Li ◽  
Yanchun Li ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Critical Role ◽  
Water Channel ◽  
Pathogenic Mechanism ◽  
Aquaporin 2 ◽  
Plasmid Transfection ◽  
Α Helix

The aquaporin 2 (AQP2) plays a critical role in water reabsorption to maintain water homeostasis. AQP2 mutation leads to nephrogenic diabetes insipidus (NDI), characterized by polyuria, polydipsia, and hypernatremia. We previously reported that a novel AQP2 mutation (G215S) caused NDI in a boy. In this study, we aimed to elucidate the cell biological consequences of this mutation on AQP2 function and clarify the molecular pathogenic mechanism for NDI in this patient. First, we analyzed AQP2 expression in Madin-Darby canine kidney (MDCK) cells by AQP2-G215S or AQP2-WT plasmid transfection and found significantly decreased AQP2-G215S expression in cytoplasmic membrane compared with AQP2-WT, independent of forskolin treatment. Further, we found co-localization of endoplasmic reticulum (ER) marker (Calnexin) with AQP2-G215S rather than AQP2-WT in MDCK cells by immunocytochemistry. The functional analysis showed that MDCK cells transfected with AQP2-G215S displayed reduced water permeability compared with AQP2-WT. Visualization of AQP2 structure implied that AQP2-G215S mutation might interrupt the folding of the sixth transmembrane α-helix and/or the packing of α-helices, resulting in the misfolding of monomer and further impaired formation of tetramer. Taken together, these findings suggested that AQP2-G215S was misfolded and retained in the ER and could not be translocated to the apical membrane to function as a water channel, which revealed the molecular pathogenic mechanism of AQP2-G215S mutation and explained for the phenotype of NDI in this patient.

p.R254Q mutation in the aquaporin-2 water channel causing dominant nephrogenic diabetes insipidus is due to a lack of arginine vasopressin-induced phosphorylation

2009 ◽  
Vol 30 (10) ◽  
pp. E891-E903 ◽  
Author(s):  
Paul JM Savelkoul ◽  
Fabrizio De Mattia ◽  
Yuedan Li ◽  
Erik-Jan Kamsteeg ◽  
Irene BM Konings ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Nephrogenic Diabetes Insipidus ◽  
Water Channel ◽  
Aquaporin 2

scholarly journals Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2

2007 ◽  
Vol 292 (5) ◽  
pp. F1334-F1344 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Jing Qu ◽  
Ken A. Volk ◽  
Patricia Kirby ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Hormonal Regulation ◽  
Nephrogenic Diabetes Insipidus ◽  
Mdck Cells ◽  
Collecting Duct ◽  
Phosphorylation Site ◽  
Water Channel ◽  
Urine Osmolality ◽  
Functional Expression ◽  
Aquaporin 2

In mammals, the hormonal regulation of water homeostasis is mediated by the aquaporin-2 water channel (Aqp2) of the collecting duct (CD). Vasopressin induces redistribution of Aqp2 from intracellular vesicles to the apical membrane of CD principal cells, accompanied by increased water permeability. Mutations of AQP2 gene in humans cause both recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. In this study, we generated a line of mice with the distal COOH-terminal tail of the Aqp2 deleted ( Aqp2Δ 230), including the protein kinase A phosphorylation site (S256), but still retaining the putative apical localization signal (221–229) at the COOH-terminal. Mice heterozygous for the truncation appear normal. Homozygotes are viable to adulthood, with reduced urine concentrating capacity, increased urine output, decreased urine osmolality, and increased daily water consumption. Desmopressin increased urine osmolality in wild-type mice but had no effect on Aqp2Δ 230/Δ 230 mice. Kidneys from affected mice showed CD and pelvis dilatation and papillary atrophy. By immunohistochemical and immunoblot analyses using antibody against the NH2-terminal region of the protein Aqp2Δ 230/Δ 230 mice had a markedly reduced protein abundance. Expression of the truncated protein in MDCK cells was consistent with a small amount of functional expression but no stimulation. Thus we have generated a mouse model of NDI that may be useful in studying the physiology and potential therapy of this disease.

Sign in / Sign up

Export Citation Format

Share Document