Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus
Abstract X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of...
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2021-05-01
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doaj-0fc457740b264d7d9a3ec219ff97a9402021-05-30T11:35:04ZengNature Publishing GroupScientific Reports2045-23222021-05-0111111210.1038/s41598-021-90736-zFunctional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidusLixia Wang0Weihong Guo1Chunyun Fang2Wenli Feng3Yumeng Huang4Xiaona Zhang5Ming Liu6Jingqiu Cui7Department of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalDepartment of Endocrinology and Metabolism, Tianjin Medical University General HospitalAbstract X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI.https://doi.org/10.1038/s41598-021-90736-z |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lixia Wang Weihong Guo Chunyun Fang Wenli Feng Yumeng Huang Xiaona Zhang Ming Liu Jingqiu Cui |
spellingShingle |
Lixia Wang Weihong Guo Chunyun Fang Wenli Feng Yumeng Huang Xiaona Zhang Ming Liu Jingqiu Cui Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus Scientific Reports |
author_facet |
Lixia Wang Weihong Guo Chunyun Fang Wenli Feng Yumeng Huang Xiaona Zhang Ming Liu Jingqiu Cui |
author_sort |
Lixia Wang |
title |
Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus |
title_short |
Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus |
title_full |
Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus |
title_fullStr |
Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus |
title_full_unstemmed |
Functional characterization of a loss-of-function mutant I324M of arginine vasopressin receptor 2 in X-linked nephrogenic diabetes insipidus |
title_sort |
functional characterization of a loss-of-function mutant i324m of arginine vasopressin receptor 2 in x-linked nephrogenic diabetes insipidus |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-05-01 |
description |
Abstract X-linked nephrogenic diabetes insipidus (X-linked NDI) is a rare inherited disease mainly caused by lost-of-function mutations in human AVPR2 gene encoding arginine vasopressin receptor 2 (V2R). Our focus of the current study is on exploration of the functional and biochemical properties of Ile324Met (I324M) mutation identified in a pedigree showing as typical recessive X-linked NDI. We demonstrated that I324M mutation interfered with the conformation of complex glycosylation of V2R. Moreover, almost all of the I324M-V2R failed to express on the cell surface due to being captured by the endoplasmic reticulum control system. We further examined the signaling activity of DDAVP-medicated cAMP and ERK1/2 pathways and the results revealed that the mutant receptor lost the ability in response to DDAVP stimulation contributed to the failure of accumulation of cAMP and phosphorylated ERK1/2. Based on the characteristics of molecular defects of I324M mutant, we selected two reagents (SR49059 and alvespimycin) to determine whether the functions of I324M-V2R can be restored and we found that both compounds can significantly “rescue” I324M mutation. Our findings may provide further insights for understanding the pathogenic mechanism of AVPR2 gene mutations and may offer some implications on development of promising treatments for patients with X-linked NDI. |
url |
https://doi.org/10.1038/s41598-021-90736-z |
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