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Intrafamilial phenotype variability in nephrogenic diabetes insipidus
Karine Kalenga1, Alexandre Persu, Eric Goffin
1Division of Nephrology, Université Catholique de Louvain Medical School, Brussels, Belgium.
Summary
A novel AVPR2 gene mutation (R137H) causes X-linked nephrogenic diabetes insipidus (NDI). This mutation, identified in a Belgian family, presented with variable NDI severity in affected males, suggesting modifier effects.
Area of Science:
- Genetics
- Endocrinology
- Nephrology
Background:
- X-linked nephrogenic diabetes insipidus (NDI) is primarily caused by AVPR2 gene mutations.
- The arginine vasopressin (AVP) receptor type 2 (V2R) mediates AVP's antidiuretic effect.
- Previously reported AVPR2 mutations rarely showed mild NDI phenotypes or intrafamilial variability.
Purpose of the Study:
- To identify the genetic cause of NDI in a Belgian family.
- To characterize the phenotype associated with a novel AVPR2 mutation.
- To investigate potential intrafamilial phenotype variability in X-linked NDI.
Main Methods:
- Genetic sequencing to identify mutations in the AVPR2 gene.
- Clinical phenotyping of affected individuals, including water deprivation and AVP analog infusion tests.
- Analysis of V2R function in response to the identified mutation.
Main Results:
- A novel R137H mutation in the AVPR2 gene was identified in two brothers and their mother.
- The R137H mutation impaired V2R's ability to stimulate adenylate cyclase.
- The proband exhibited severe NDI, while his brother presented with a milder phenotype and preserved urinary concentrating ability.
- This represents the first reported instance of intrafamilial phenotype variability for an AVPR2 mutation.
Conclusions:
- The R137H AVPR2 mutation can cause both severe and mild forms of X-linked NDI within the same family.
- Genetic or environmental factors may modify the clinical expression of the R137H mutation.
- Further research is needed to elucidate the mechanisms underlying phenotype variability in X-linked NDI.