Novel and recurrent variants in AVPR2 in 19 families with X-linked congenital nephrogenic diabetes insipidus

Joshi, Shivani; Kvistgaard, Helene; Kamperis, Konstantinos; Faerch, Mia; Hagstrøm, Søren; Gregersen, Niels; Rittig, Søren; Christensen, Jane H.

doi:10.1007/s00431-018-3132-z

Cited by 13 publications

(11 citation statements)

References 13 publications

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“…This mutation may disrupt the structure of the extracellular domain and reduce the recognition and binding of AVP, and finally break the water homeostasis and lead to NDI. Our study is consistent with a previous study that mutations in the AVPR2 third extracellular domain can result in NDI [Joshi et al, 2018]. Similar mutations located in this domain have been reported in NDI patients, such as p.R181C and p.S187R [Pan et al, 1992;Boson et al, 2006].…”

Section: Discussionsupporting

confidence: 93%

Identification of a Novel Arginine Vasopressin Receptor 2 Mutation (p.V183M) in a Chinese Family with Nephrogenic Diabetes Insipidus

et al. 2020

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Loss of function of arginine vasopressin receptor 2 (AVPR2) may affect the recognition and binding of arginine vasopressin (AVP) which, in turn, may prevent the activation of Gs/ adenylate cyclase and reduce the reabsorption of water by renal tubules and combined tubes. Finally, the organism may suffer from nephrogenic diabetes insipidus (NDI), a kind of kidney disorder featured by polyuria and polydipsia, due to a break of water homeostasis. In this study, we enrolled a Chinese family with polyuria and polydipsia. The proband presented abnormal fluid intake and excessive urine output. A water deprivation and AVP stimulation test further indicated that this patient had NDI. By sequencing known causative genes for diabetes insipidus, we identified a novel mutation in AVPR2 (c.547G>A; p.V183M) in the family. This mutation, located in a conserved site of AVPR2 and predicted to be disease-causing by informatics programs, was absent in our 200 controls and other public databases. Our study not only further confirms the clinical diagnosis, but also expands the spectrum of AVPR2 mutations and contributes to genetic diagnosis and counseling of patients with NDI.

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Section: Discussionsupporting

confidence: 93%

Identification of a Novel Arginine Vasopressin Receptor 2 Mutation (p.V183M) in a Chinese Family with Nephrogenic Diabetes Insipidus

et al. 2020

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“…Optimizing the diagnostic strategy especially with regard to genetic analysis was one of our top priorities. It has been well-established that the heterozygous loss-of-function variants o f AVPR2 or AQP2 are common disease-causing genes that result in congenital NDI ( 2 , 3 , 20 ). In order to try to elucidate the pathogenicity of variants of AVPR2 or AQP2 , we compared population SNPs with pathogenic mutations from the HGMD.…”

Section: Discussionmentioning

confidence: 99%

“…In 90% of patients, inheritance of NDI arises from mutations in the X-linked gene coding for the vasopressin type 2 receptor ( AVPR2 ) (OMIM # 304800 ) ( 1 , 2 ). The remaining patients display autosomal recessive or dominant forms of inheritance due to mutations in the gene coding for the aquaporin 2 ( AQP2 ) water channel (OMIM # 222000 ; OMIM # 125800 , respectively) ( 1 , 3 ). The main clinical hallmarks of NDI are polyuria and compensatory polydipsia.…”

Section: Introductionmentioning

confidence: 99%

Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

Liao

Xiang

et al. 2021

Front. Pediatr.

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Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.

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“…Optimizing the diagnostic strategy including genetic analysis is one of our top priorities. As is known disease-causing genes for NDI, it has been well established the heterozygous loss of function variants of AVPR2 or AQP2 result in congenital NDI 2,3,20 . In order to try to elucidate the pathogenicity of variants of AVPR2 or AQP2, we compared population SNPs with pathogenic mutations from HGMD.…”

Section: Discussionmentioning

confidence: 99%

“…Inheritance is X-linked in 90% of patients due to mutations in the gene coding for the vasopressin type 2 receptor (AVPR2) (OMIM #304800) 1,2 . The remaining patients have autosomal recessive or dominant forms due to mutations in the gene coding for the water channel aquaporin 2 (AQP2) (OMIM #222000; OMIM #125800) 1,3 . The main clinical hallmarks of NDI are polyuria and compensatory polydipsia.…”

Section: Introductionmentioning

confidence: 99%

Integrating population variation and protein structural analysis to improve the clinical genetic diagnosis and treatment in children with congenital nephrogenic diabetes insipidus

Liao¹,

Xiang²,

Li³

et al. 2020

Preprint

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Background and Objectives: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. Establishing the genetic diagnosis appears particularly important to NDI for early detection and differential diagnosis.Method: We utilized a Chinese multicenter registry to investigate genotype and phenotype in children with NDI from 2014 to 2019. The structural locations of the pathogenic mutations from this study and the literature, as well as population variants retried from gnomAD were analyzed. Results: A total of 10 boys from 9 families carried mutations in AVPR2 (8/10) or AQP2 (2/10). Another 7 relatives of the families were diagnosed by sequencing for partial or subclinical NDI. Patients presented with dehydration, polyuria-polydipsia, and severe hypernatremia with a median age at diagnosis of 1.0 month (IQR 0.16, 18). Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane regions of AVPR2, and enrichment of diagnostic mutations by autosomal dominant inheritance (AD) in the C terminal region of AQP2. The pathogenic mutations are significantly more likely to be buried inside the domain comparing the population variants. Through structural analysis and in silico prediction, the eight mutations identified in this study were considered as presumably disease causative. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment of hypernatremic dehydration in neonates should not choose the isotonic saline as a rehydration fluid.Conclusion: Genetic analysis presumably confirmed the diagnosis of NDI in every patient of the studied cohort. A plea of early identifying NDI confirmed by phenotype and genotype, and consequently optimize the treatment.

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Novel and recurrent variants in AVPR2 in 19 families with X-linked congenital nephrogenic diabetes insipidus

Cited by 13 publications

References 13 publications

Identification of a Novel Arginine Vasopressin Receptor 2 Mutation (p.V183M) in a Chinese Family with Nephrogenic Diabetes Insipidus

Identification of a Novel Arginine Vasopressin Receptor 2 Mutation (p.V183M) in a Chinese Family with Nephrogenic Diabetes Insipidus

Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

Integrating population variation and protein structural analysis to improve the clinical genetic diagnosis and treatment in children with congenital nephrogenic diabetes insipidus

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