Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level

Yi Fu, Tim Cheetham, David Bourn, Eric Orwoll, David Cohen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency <0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability.

Original languageEnglish (US)
Pages (from-to)210-216
Number of pages7
JournalPhysiological Genomics
Volume45
Issue number6
DOIs
StatePublished - 2013

Fingerprint

Arginine
Sodium
Serum
Gene Frequency
Population
Nephrogenic Diabetes Insipidus
Vasopressin Receptors
X-Linked Genes
Mutation
Osteoporotic Fractures
Water
Vasopressins
Proteins
Alleles
Demography
Urine
Phenotype

Keywords

  • Arginine vasopressin
  • Hypernatremia
  • Hyponatremia
  • Osmoregulation

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

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title = "Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level",
abstract = "The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency <0.06{\%}. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability.",
keywords = "Arginine vasopressin, Hypernatremia, Hyponatremia, Osmoregulation",
author = "Yi Fu and Tim Cheetham and David Bourn and Eric Orwoll and David Cohen",
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T1 - Functional polymorphisms affecting the clinically important arginine-137 residue of AVPR2 do not influence serum sodium concentration at the population level

AU - Fu, Yi

AU - Cheetham, Tim

AU - Bourn, David

AU - Orwoll, Eric

AU - Cohen, David

PY - 2013

Y1 - 2013

N2 - The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency <0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability.

AB - The protein product of the AVPR2 gene, coding for the arginine vasopressin receptor type 2, is essential for vasopressin-dependent concentration of the urine. The arginine residue at position 137 in the protein product of this gene is uniquely pivotal for function. The R137H mutant inactivates the receptor conferring congenital nephrogenic diabetes insipidus, whereas activating mutations at this same residue (i.e., R137C and R137L) confer pathological water retention in the nephrogenic syndrome of inappropriate antidiuresis. These mutations were discovered in human subjects with conspicuous phenotypes in clinical water balance. Prevalence of these polymorphisms among asymptomatic individuals has not been assessed, nor has their contribution to broad interindividual variation in serum sodium concentration; no data addressing minor allele frequency are available. We genotyped two large cohorts using a validated high-throughput Pyrosequencing-based assay that we designed to capture the totality of pathological variation at this important residue. In the Osteoporotic Fractures in Men (MrOS) Study, all participants were male (i.e., hemizygous for AVPR2 gene on the X-chromosome), and participants were oversampled at the extremes of the population distribution for serum sodium concentration. In the Offspring Cohort of the Framingham Heart Study, male and female participants were genotyped. No pathological variants affecting R137 were detected among the 5,142 AVPR2 alleles successfully genotyped. Even at the population extremes of serum sodium distribution, we estimate minor allele frequency <0.06%. We conclude that these disease-associated variants are exceedingly uncommon and do not contribute broadly to interindividual variability in serum sodium concentration or to its heritability.

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