Vasopressin Receptor Mutations in Nephrogenic Diabetes Insipidus

doi:10.1016/j.semnephrol.2008.03.005

Seminars in Nephrology

Volume 28, Issue 3, May 2008, Pages 245-251

https://doi.org/10.1016/j.semnephrol.2008.03.005 Get rights and content

Summary

The purpose of this review is first to describe the importance of early detection of vasopressin receptor mutations responsible for X-linked nephrogenic diabetes insipidus (NDI). We have proposed that all families with hereditary diabetes insipidus should have their molecular defect identified because early diagnosis and treatment of affected infants can avert the physical and mental retardation that results from repeated episodes of dehydration. Secondly, 95 published missense mutations responsible for X-linked NDI are likely to result in misfolded arginine-vasopressin V₂ receptors that are trapped in the endoplasmic reticulum. These misfolded receptors are unable to reach the plasma membrane in principal collecting duct cells and to engage the circulating antidiuretic hormone, arginine-vasopressin. These misfolded proteins potentially could be rescued with pharmacologic chaperones, an active area of research pertinent to other hereditary protein misfolding diseases such as cystic fibrosis, phenylketonuria, and Anderson-Fabry disease among many others. Finally, a long-term careful surveillance of all patients with hereditary NDI should be performed to prevent chronic renal failure likely caused by the long-term functional tract obstruction with reflux.

Section snippets

AVPR2 is a GPCR

Loss-of-function of either of these proteins will result in NDI. The V2 receptor is one of 701 members of the rhodopsin family within the superfamily of guanine-nucleotide (G) protein-coupled receptors (GPCRs) (Fig. 1).1, 2 GPCRs represent the largest family of membrane proteins in the human genome. They are remarkably versatile signaling molecules that are responsible for the majority of transmembrane signal transduction in response to hormones and neurotransmitters. GPCRs share a common

X-Linked NDI (OMIM 304800): Loss-of-Function of AVPR2, Misfolding, and Functional Rescue with Pharmacologic Chaperones

X-linked NDI is generally a rare disease in which the affected male patients do not concentrate their urine after administration of AVP.¹⁶ Because this form is a rare, recessive, X-linked disease, female individuals are unlikely to be affected, but heterozygous females can show variable degrees of polyuria and polydipsia because of skewed X-chromosome inactivation. In Quebec, the incidence of this disease among male individuals was estimated to be approximately 8.8 in 1,000,000 male live births.

Large Dilatation of the Urinary Tract and Bladder Could Lead to Reflux and Chronic Renal Failure

All polyuric states (whether neurogenic, nephrogenic, or psychogenic) can induce large dilatations of the urinary tract and bladder, and bladder function impairment has been well documented in patients who bear AVPR2 or AQP2 mutations (Fig. 4).26, 27 Of interest, an inducible mouse model of NDI was produced recently by floxed Aqp2 gene deletion,²⁸ which also showed evidence of structural damage from the sustained polyuria. Chronic renal failure secondary to bilateral hydronephrosis has been

Acknowledgments

The author thanks Ivana Arapovic for secretarial assistance.

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: This study was supported by the Canadian Institutes of Health Research, and by the Kidney Foundation of Canada. Dr. Bichet holds a Canada Research Chair in Genetics of Renal Diseases.

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Vasopressin Receptor Mutations in Nephrogenic Diabetes Insipidus

Summary

Section snippets

AVPR2 is a GPCR

X-Linked NDI (OMIM 304800): Loss-of-Function of AVPR2, Misfolding, and Functional Rescue with Pharmacologic Chaperones

Large Dilatation of the Urinary Tract and Bladder Could Lead to Reflux and Chronic Renal Failure

Acknowledgments

Trends Mol Med

J Biol Chem

J Biol Chem

Cell

J Biol Chem

The G-protein-coupled receptors in the human genome form five main familiesPhylogenetic analysis, paralogon groups, and fingerprints

Mol Pharmacol

The evolutionarily triumphant G-protein-coupled receptor

Mol Pharmacol

Crystal structure of the human beta2 adrenergic G-protein-coupled receptor

Nature

High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

Science

GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

Science

Aquaporins in the kidney: from molecules to medicine

Physiol Rev

Localized effects of cAMP mediated by distinct routes of protein kinase A

Physiol Rev

Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes

Science

Mutation of an A-kinase-anchoring protein causes long-QT syndrome

Proc Natl Acad Sci U S A

Urea and urine concentrating ability: new insights from studies in mice

Am J Physiol Renal Physiol