Nephrogenic diabetes insipidus pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor in Chief: Cafer Zorkun, M.D., Ph.D. [2]
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Overview
Pathophysiology
Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.
Genetics
- AVPR2. A gain-of-function mutation in AVPR2 was reported to produce an abnormality called "nephrogenic syndrome of inappropriate antidiuresis" [Feldman et al 2005, Knoers 2005].
- AQP2. No other phenotypes are known to be associated with mutations in AQP2.
Genotype-Phenotype Correlations
X-linked and recessive NDI are similar with respect to initial symptoms and, with a few exceptions, age of onset.
In the minority of individuals with X-linked NDI and a V2 receptor mutation resulting in partial insensitivity to AVP or DDAVP, the disease onset may be later in childhood. Thus, three families had the missense mutation D85N associated with decreased ligand-binding affinity and decreased coupling to Gs, and one had the missense mutation G201D associated with a decreased number of cell surface AVPR2 receptors [Sadeghi et al 1997]. An individual representing a simplex case (a single affected individual in a family) had the mutation P322S, which was able to partly activate the Gs/adenylyl cyclase system [Ala et al 1998].
Mode of Inheritance
Nephrogenic diabetes insipidus (NDI) may be transmitted in an X-linked recessive manner (90% of families), an autosomal recessive manner (~9% of families), or an autosomal dominant manner (~1% of families).
Risk to Family Members — X-Linked Inheritance
Parents of a proband
- The father of an affected male will not have NDI nor will he be a carrier of the mutation.
- Women who have an affected son and another affected male relative are obligate heterozygotes.
- A positive family history consistent with X-linked inheritance is observed in about half of X-linked cases [Arthus et al 2000].
- Pedigree analysis reveals that in about half of families with an affected male, he represents a simplex case (i.e., an affected individual with no known family history of NDI); several possibilities regarding his mother's carrier status need to be considered:
- The proband has a de novo disease-causing mutation in the AVPR2 gene and his mother is not a carrier;
- His mother has a de novo disease-causing mutation in the AVPR2 gene, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body) or (b) as "germline mosaicism" (i.e., in some of her germ cells only);
- His maternal grandmother has a de novo disease-causing mutation in the AVPR2 gene.
Sibs of a proband
- The risk to sibs depends upon the genetic status of the proband's mother.
- If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.
- If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because the possibility of germline mosaicism exists.
Offspring of a proband
All the daughters of an affected male are carriers; none of his sons will be affected.
Carrier Detection
Carrier testing by molecular analysis of at-risk female relatives is available if the mutation has been identified in the proband.
Risk to Family Members — Autosomal Recessive Inheritance
Parents of a proband
- The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation in the AQP2 gene.
- Heterozygotes are asymptomatic.
Sibs of a proband
- At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
- Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
- Heterozygotes (carriers) are asymptomatic.
Offspring of a proband.
- The offspring of an individual with autosomal recessive NDI are obligate heterozygotes (carriers) for a disease-causing mutation in the AQP2 gene.
Other family members
Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing by molecular analysis for at-risk family members is available once the mutations have been identified in the proband.
Risk to Family Members — Autosomal Dominant Inheritance
Parents of a proband
- The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small.
- A proband with autosomal dominant NDI may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.
Sibs of a proband
- The risk to sibs depends upon the genetic status of the proband's parent.
- If a parent of a proband is affected, the risk to the sibs is 50%.
- When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Offspring of a proband
- Each child of an individual with autosomal dominant NDI has a 50% chance of inheriting the AQP2 mutation.
Other family members of a proband
- The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.