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

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 fro...

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Autores principales: Liao, Panli, Xiang, Tianchao, Li, Hongxia, Fang, Ye, Fang, Xiaoyan, Zhang, Zhiqing, Cao, Qi, Zhai, Yihui, Chen, Jing, Xu, Linan, Liu, Jialu, Tang, Xiaoshan, Liu, Xiaorong, Wang, Xiaowen, Luan, Jiangwei, Shen, Qian, Chen, Lizhi, Jiang, Xiaoyun, Ma, Duan, Xu, Hong, Rao, Jia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116627/
https://www.ncbi.nlm.nih.gov/pubmed/33996673
http://dx.doi.org/10.3389/fped.2021.566524
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author Liao, Panli
Xiang, Tianchao
Li, Hongxia
Fang, Ye
Fang, Xiaoyan
Zhang, Zhiqing
Cao, Qi
Zhai, Yihui
Chen, Jing
Xu, Linan
Liu, Jialu
Tang, Xiaoshan
Liu, Xiaorong
Wang, Xiaowen
Luan, Jiangwei
Shen, Qian
Chen, Lizhi
Jiang, Xiaoyun
Ma, Duan
Xu, Hong
Rao, Jia
author_facet Liao, Panli
Xiang, Tianchao
Li, Hongxia
Fang, Ye
Fang, Xiaoyan
Zhang, Zhiqing
Cao, Qi
Zhai, Yihui
Chen, Jing
Xu, Linan
Liu, Jialu
Tang, Xiaoshan
Liu, Xiaorong
Wang, Xiaowen
Luan, Jiangwei
Shen, Qian
Chen, Lizhi
Jiang, Xiaoyun
Ma, Duan
Xu, Hong
Rao, Jia
author_sort Liao, Panli
collection PubMed
description 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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spelling pubmed-81166272021-05-14 Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus Liao, Panli Xiang, Tianchao Li, Hongxia Fang, Ye Fang, Xiaoyan Zhang, Zhiqing Cao, Qi Zhai, Yihui Chen, Jing Xu, Linan Liu, Jialu Tang, Xiaoshan Liu, Xiaorong Wang, Xiaowen Luan, Jiangwei Shen, Qian Chen, Lizhi Jiang, Xiaoyun Ma, Duan Xu, Hong Rao, Jia Front Pediatr Pediatrics 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. Frontiers Media S.A. 2021-04-29 /pmc/articles/PMC8116627/ /pubmed/33996673 http://dx.doi.org/10.3389/fped.2021.566524 Text en Copyright © 2021 Liao, Xiang, Li, Fang, Fang, Zhang, Cao, Zhai, Chen, Xu, Liu, Tang, Liu, Wang, Luan, Shen, Chen, Jiang, Ma, Xu and Rao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Liao, Panli
Xiang, Tianchao
Li, Hongxia
Fang, Ye
Fang, Xiaoyan
Zhang, Zhiqing
Cao, Qi
Zhai, Yihui
Chen, Jing
Xu, Linan
Liu, Jialu
Tang, Xiaoshan
Liu, Xiaorong
Wang, Xiaowen
Luan, Jiangwei
Shen, Qian
Chen, Lizhi
Jiang, Xiaoyun
Ma, Duan
Xu, Hong
Rao, Jia
Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title_full Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title_fullStr Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title_full_unstemmed Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title_short Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus
title_sort integrating population variants and protein structural analysis to improve clinical genetic diagnosis and treatment in nephrogenic diabetes insipidus
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116627/
https://www.ncbi.nlm.nih.gov/pubmed/33996673
http://dx.doi.org/10.3389/fped.2021.566524
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