Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family

Boccalandro, Cristina; Mattia, Fabrizio De; Guo, Dong; Xue, Li; Orlander, Philip R.; King, Terri M.; Gupta, Prateek; Deen, Peter M.T.; Lavis, Victor R.; Milewicz, Dianna M.

doi:10.1097/01.asn.0000125248.85135.43

Cited by 28 publications

(16 citation statements)

References 38 publications

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“…Upon expression in collecting duct cells, both AQP2-D150E and AQP2-G215C appeared to be retained in the ER, as a 32-kDa high-mannose glycosylated band, characteristic of ER-retarded AQP2 mutants in recessive NDI, was observed [4, 15, 29]. Consistently, immunolocalization studies of both AQP2-D150E and AQP2-G215C displayed a high degree of colocalization with calnexin, a specific ER marker.…”

Section: Discussionmentioning

confidence: 54%

Characterization of Two Novel Missense Mutations in the <i>AQP2 </i>Gene Causing Nephrogenic Diabetes Insipidus

et al. 2006

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Here, we report the aquaporin 2 (AQP2) mutational analysis of a patient with nephrogenic diabetes insipidus heterozygote due to two novel missense mutations. Direct sequencing of DNA in the male patient revealed that he was compound heterozygote for two mutations in the AQP2 gene: a thymine-to-adenine transversion at position 450 (c.450T>A) in exon 2 and a guanine-to-thymine at nucleotide position 643 (c.643G>T) in exon 4. The double heterozygous 450T>A and 643G>T transversion causes the amino acid substitution D150E and G215C. Direct sequencing of exons 2 and 4 of the AQP2 gene from each of the parents revealed that the c.450T>A mutation was inherited from the father while the c.643G>T mutation was inherited from the mother. Analysis of AQP2 excretion demonstrated that no AQP2 was detectable in the urine of the proband, whereas normal AQP2 levels were measured in both parents. When expressed in renal cells, both proteins were retarded in the endoplasmic reticulum and no redistribution was observed after forskolin stimulation. Of note, homology modeling revealed that the two mutations involve two highly conserved residues providing important clues about the role of the wt residues in AQP2 stability and function.

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Section: Discussionmentioning

confidence: 54%

Characterization of Two Novel Missense Mutations in the <i>AQP2 </i>Gene Causing Nephrogenic Diabetes Insipidus

et al. 2006

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“…The literature reports that approximately 10% of CNDI cases are attributable to mutations in the AQP2. 18 Patients with CNDI due to recessive AQP2 mutations are often compound heterozygotes. 19 We report here two families with homozygous mutations in AQP2, which is not surprising given the presence of consanguinity.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations underlying nephrogenic diabetes insipidus in Arab families

Carroll

Al-Mojalli

Al-Abbad

et al. 2006

Genetics in Medicine

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Purpose: Nephrogenic Diabetes Insipidus (NDI) is genetically heterogeneous and may be inherited in an X-linked or autosomal recessive manner. We aimed to investigate the molecular basis of NDI among Arab families.Methods: Direct sequencing of coding regions for AQP2 and AVPR2 was used to identify underlying mutations. One large deletion required Southern blot analysis and a PCR-based strategy to identify deletion junctions. Results: We identified two novel missense mutations (AQP2:p.Gly100Arg and p.Gly180Ser) in AQP2 and one novel missense mutation (AVPR2:p.Gly122Asp), one previously reported missense mutation (AVPR2:p.Arg137His) and one novel contiguous deletion (AVPR2:c.25 ϩ 273_ARHGAP4o:2650-420del) affecting AVPR2. We also describe evidence of lyonization associated with the novel deletion. Conclusions: Two novel mutations were identified in each of AVPR2 and AQP2 underlying CNDI in Arab families. Identification of these mutations will facilitate early diagnosis of CNDI, counseling of families and provide opportunities for early intervention aimed at reducing morbidity. The presence of affected females and consanguinity, as is often observed in Arab communities should not be used to rule out AVPR2 as a candidate when considering diagnostic testing. Careful observation of phenotypic heterogeneity should be used in referring such families for both AQP2 and AVPR2 molecular genetic testing. Genet Med 2006:8(7):443-447.

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“…principal cells of the patient, because of the following: Upon expression in oocytes and MDCK cells, AQP2-R254L was a functional water channel but was retained in the cell. However, it was not retained in the ER, as a 32-kD high-mannose glycosylation band, which is characteristic for ER-retained AQP2 mutants in recessive NDI (13,24,25), was not observed ( Figure 2). Also, AQP2-R254L formed heteroligomers with wt-AQP2 in oocytes ( Figure 2) and MDCK cells ( Figure 4C) and impaired the further trafficking of wt-AQP2 to the plasma membrane ( Figure 4B).…”

Section: Lack Of S256 Phosphorylation Likely Is the Molecular Cause Omentioning

confidence: 99%

Lack of Arginine Vasopressin–Induced Phosphorylation of Aquaporin-2 Mutant AQP2-R254L Explains Dominant Nephrogenic Diabetes Insipidus

Mattia

Savelkoul

Kamsteeg

et al. 2005

Journal of the American Society of Nephrology

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Water homeostasis in humans is regulated by vasopressin, which induces the translocation of homotetrameric aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells. For this process, phosphorylation of AQP2 at S256 by cAMP-dependent protein kinase A is thought to be essential. Mutations in the AQP2 gene cause recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Here, a family in which dominant NDI was caused by an exchange of arginine 254 by leucine in the intracellular C terminus of AQP2 (AQP2-R254L), which destroys the protein kinase A consensus site, was identified. Expressed in oocytes, AQP2-R254L appeared to be a functional water channel but was impaired in its transport to the cell surface to the same degree as AQP2-S256A, which mimics nonphosphorylated AQP2. In polarized renal cells, AQP2-R254L was retained intracellularly and was distributed similarly as AQP2-S256A or wild-type AQP2 in unstimulated cells. Upon co-expression in MDCK cells, AQP2-R254L interacted with and retained wild-type AQP2 in intracellular vesicles. Furthermore, AQP2-R254L had a low basal phosphorylation level, which was not increased with forskolin, and mimicking constitutive phosphorylation in AQP2-R254L with the S256D mutation shifted its expression to the basolateral and apical membrane. These data indicate that dominant NDI in this family is due to a R254L mutation, resulting in the loss of arginine vasopressin-mediated phosphorylation of AQP2 at S256, and illustrates the in vivo importance of phosphorylation of AQP2 at S256 for the first time. I n hypernatremia or hypovolemia, arginine vasopressin (AVP) release from the pituitary is increased to restore a proper water balance. In renal collecting ducts, AVP will bind to the vasopressin-2 receptor (AVPR2) located in the basolateral membrane, which will induce a transient increase in intracellular cAMP, which in turn increases protein kinase A (PKA) activity. PKA then is thought to phosphorylate several proteins, including aquaporin-2 (AQP2) water channels, which reside in intracellular vesicles. Phosphorylated AQP2 (p-AQP2) then redistributes to the apical membrane, which renders the cells water permeable. Driven by the transcellular osmotic gradient, water from the glomerular filtrate then enters the cells via AQP2 and leaves the cells to the interstitium via AQP3 and AQP4, located in the basolateral membrane, thereby restoring isotonicity and euvolemia (1,2).Mutations in the AQP2 gene cause autosomal recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is resistant to the action of AVP (3,4). Expression studies revealed that AQP2 mutants in dominant NDI are properly folded but are missorted. This sorting defect is also present in heteroligomers of mutant and wild-type (wt) AQP2, which explains the dominant negative effect. Depending on the mutation, however, the mutants in dominant NDI are mis...

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Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family

Cited by 28 publications

References 38 publications

Characterization of Two Novel Missense Mutations in the <i>AQP2 </i>Gene Causing Nephrogenic Diabetes Insipidus

Characterization of Two Novel Missense Mutations in the <i>AQP2 </i>Gene Causing Nephrogenic Diabetes Insipidus

Novel mutations underlying nephrogenic diabetes insipidus in Arab families

Lack of Arginine Vasopressin–Induced Phosphorylation of Aquaporin-2 Mutant AQP2-R254L Explains Dominant Nephrogenic Diabetes Insipidus

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