Diverse vasopressin V2 receptor functionality underlying partial congenital nephrogenic diabetes insipidus

Faerch, Mia; Christensen, Jane H.; Rittig, Søren; Johansson, Jan‐Ove; Gregersen, Niels; Zegher, Francis de; Corydon, Thomas J.

doi:10.1152/ajprenal.00331.2009

Cited by 18 publications

(10 citation statements)

References 28 publications

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“…However, the principal indication of possible NDI was the high basal AVP levels in both cases. Only nine mutants, including those identified herein, have been reported previously as causative for partial NDI, whereas more than 200 mutants have been identified as causal for complete NDI (11). It is thus possible that partial NDI will be revealed in further patients with polydipsia and that additional V2R mutations will be found.…”

Section: Discussionmentioning

confidence: 78%

“…Inactivating mutations of V2 receptor (V2R) are responsible for about 90% of congenital NDI cases and are transmitted in a cross-linked manner, thus manifesting as a complete loss of function phenotype in most instances. Among the more than 200 V2R mutations identified to date, however, only seven have been reported to cause a partial congenital NDI phenotype in clinical cases (5)(6)(7)(8)(9)(10)(11).…”

Section: Inactivating Mutations Of the V2 Vasopressin Receptor (V2r) mentioning

confidence: 99%

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V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists

Takahashi

Makita

Manaka

et al. 2012

Journal of Biological Chemistry

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Background: Inactivating mutations of the V2 receptor (V2R) cause nephrogenic diabetes insipidus (NDI). Results: Two V2R mutants discovered in partial NDI show partial defects, and V2R antagonists rescued them. Conclusion: V2R antagonists operate as pharmacochaperones for defective mutants, whereas they operate as inverse agonists for normal receptors. Significance: V2R antagonists can act as protean agonists, potentially underlying their dual effects.

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Section: Discussionmentioning

confidence: 78%

Section: Inactivating Mutations Of the V2 Vasopressin Receptor (V2r) mentioning

confidence: 99%

V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists

Takahashi

Makita

Manaka

et al. 2012

Journal of Biological Chemistry

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“…The slides to be analyzed by confocal laser scanning microscopy (CLSM) were added 1 μM TO-PRO-3 (Molecular Probes, Invitrogen) in PBS for 5 minutes to stain the DNA and washed twice in PBS as previously described [40]. The slides were added anti-fade mounting medium (VECTASHIELD® Mounting Medium from VECTOR laboratories) and sealed.…”

Section: Methodsmentioning

confidence: 99%

An eEF1A1 truncation encoded by PTI-1 exerts its oncogenic effect inside the nucleus

et al. 2014

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BackgroundThe oncogene PTI-1 was originally isolated from a prostate cancer cell line by its capability to transform rat fibroblasts. The PTI-1 mRNA has a very eccentric structure as the 5′UTR is similar to prokaryotic 23S rRNA, while the major open reading frame and the 3′UTR corresponds to a part of the mRNA encoding human translation elongation factor eEF1A1. Thus, the largest open reading frame encodes a truncated version of eEF1A1 lacking the first 67 amino acids, while having three unique N-terminal amino acids. Previously, the UTRs were shown to be a prerequisite for the transforming capacity of the PTI-1 transcript. In this study, we have investigated the possible role of the UTRs in regulating protein expression and localization.MethodsThe protein expression profiles of a number of PTI-1 mRNA variants were studied in vitro and in vivo. Furthermore, the oncogenic potentials of the same PTI-1 mRNAs were determined by monitoring the capacities of stably transfected cells expressing these mRNAs to induce tumors in nude mice and form foci in cell culture. Finally, the cellular localizations of PTI-1 proteins expressed from these mRNAs were determined by fluorescence microscopy.ResultsThe PTI-1 mRNA was found to give rise to multiple protein products that potentially originate from translation initiation at downstream, inframe AUGs within the major open reading frame. At least one of the truncated protein variants was also found to be oncogenic. However, the UTRs did not appear to influence the amount and identities of these truncated protein products. In contrast, our localization studies showed that the UTRs of the transcript promote a nuclear localization of the encoded protein(s).ConclusionsTranslation of the PTI-1 mRNA results in multiple protein products of which (a) truncated variant(s) may play a predominant role during cellular transformation. The PTI-1 UTRs did not seem to play a role in translation regulation, but appeared to contribute to a nuclear localization of the PTI-1 protein(s). This indicates that the PTI-1 protein(s) exert(s) its/their oncogenic function inside the nucleus.

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“…The amino acids are depicted in an approximate location. Illustration adapted from Faerch et al [ 15 ].…”

Section: Figmentioning

confidence: 99%

Novel de novo AVPR2 Variant in a Patient with Congenital Nephrogenic Diabetes Insipidus

Joshi

Brandström²,

Gregersen

et al. 2017

Case Rep Nephrol Dial

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Early diagnosis and treatment of congenital nephrogenic diabetes insipidus (CNDI) are essential due to the risk of intellectual disability caused by repeated episodes of dehydration and rapid rehydration. Timely genetic testing for disease-causing variants in the arginine vasopressin receptor 2 (AVPR2) gene is possible in at-risk newborns with a known family history of X-linked CNDI. In this study, a Swedish male with no family history was diagnosed with CNDI at 6 months of age during an episode of gastroenteritis. We analyzed the coding regions of AVPR2 by PCR and direct DNA sequencing and identified an 80-bp duplication in exon 2 (GenBank NM_000054.4; c.800_879dup) in the proband. This variant leads to a frameshift and introduces a stop codon four codons downstream (p.Ala294Profs*4). The variant gene product either succumbs to nonsense-mediated decay or is translated to a truncated nonfunctional vasopressin V2 receptor. This variant was absent in four unaffected family members, including his parents, as well as in 100 alleles from healthy controls, and is thus considered a novel de novo disease-causing variant. Identification of the disease-causing variant facilitated precise diagnosis of CNDI in the proband. Furthermore, it allows future genetic counseling in the family. This case study highlights the importance of genetic testing in sporadic infant cases with CNDI that can occur due to de novo variants in AVPR2 or several generations of female transmission of the disease-causing variant.

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Diverse vasopressin V2 receptor functionality underlying partial congenital nephrogenic diabetes insipidus

Cited by 18 publications

References 28 publications

V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists

V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists

An eEF1A1 truncation encoded by PTI-1 exerts its oncogenic effect inside the nucleus

Novel de novo AVPR2 Variant in a Patient with Congenital Nephrogenic Diabetes Insipidus

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