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AVPR2
arginine vasopressin receptor 2
The AVPR2 gene encodes the arginine vasopressin receptor 2, a protein crucial for regulating the body's water balance by controlling kidney water reabsorption. AVPR2 provides instructions for creating the vasopressin V2 receptor, which plays a vital role in the kidneys.
AVPR2 is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The AVPR2 gene is responsible for producing the arginine vasopressin receptor 2, often referred to as the vasopressin V2 receptor. This receptor is primarily located in the collecting ducts of the kidney, which are small tubes that facilitate the movement of water from the forming urine back into the bloodstream.
This function is crucial for maintaining appropriate fluid balance and preventing excessive water loss. Dysregulation of the AVPR2 gene can lead to conditions affecting the kidney's ability to concentrate urine.
What the gene does
The AVPR2 gene directs the synthesis of the vasopressin V2 receptor, which works in conjunction with arginine vasopressin (AVP), also known as antidiuretic hormone. This interaction is key to the body's water regulation system. When the body needs to retain more water, such as during low fluid intake or significant fluid loss through sweating, AVP is released from the brain.
Once AVP binds to the V2 receptor in the kidneys, it initiates a series of chemical reactions that prompt the kidneys to reabsorb water, thereby concentrating the urine. Conversely, when hydration is sufficient, less AVP is secreted, allowing the kidneys to excrete a larger volume of more dilute urine. This intricate mechanism ensures the body maintains appropriate hydration levels. Variants in AVPR2 can disrupt this process, impairing the kidney's ability to respond to AVP and leading to conditions characterised by significant water loss.
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Chromosome location
The AVPR2 gene is situated on the long arm of the X chromosome, specifically at position Xq28. As an X-linked gene, its inheritance pattern means that conditions associated with AVPR2 variants typically affect males more severely than females.
Protein structure
The AVPR2 protein consists of 371 amino acids. It features several regions of structural flexibility, including a Disordered region spanning amino acids 1-30, another Disordered region from amino acids 240-259, and a third Disordered region located at amino acids 349-371. Additionally, a P-X-P-P motif is present between amino acids 360 and 363, which may be involved in protein-protein interactions or signalling pathways.
Key variants
Variants within the AVPR2 gene have been identified that can affect the receptor's ability to respond to arginine vasopressin, disrupting the body's water balance mechanism. Hundreds of such variants have been documented in individuals with arginine vasopressin resistance. These genetic changes interfere with normal kidney function, preventing proper water reabsorption.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.130C>T | p.Leu44Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.135_136del | p.Ile46fs | Pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.152_159del | p.Val51fs | Pathogenic | ★★☆☆ | Nephrogenic diabetes insipidus |
c.212G>A | p.Trp71Ter | Pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.262G>A | p.Val88Met | Pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.500C>T | p.Ser167Leu | Pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.513C>G | p.Ser171Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.604C>T | p.Arg202Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubulopathies |
c.614_615del | p.Tyr205fs | Pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
c.832GTC[1] | p.Val279del | Pathogenic/Likely pathogenic | ★★☆☆ | Diabetes insipidus, nephrogenic, X-linked |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the AVPR2 gene are primarily associated with nephrogenic diabetes insipidus (X-linked). This inherited condition means the kidneys struggle to properly reabsorb water, leading to symptoms such as excessive urination and thirst as the body attempts to compensate for fluid loss. Research suggests variants in AVPR2 may also be associated with other kidney disorders, though the primary recognised condition is nephrogenic diabetes insipidus.
- Nephrogenic diabetes insipidus (X-linked) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic AVPR2 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
The AVPR2 gene is recognised within the NHS Genomic Medicine Service due to its association with inherited conditions. It is listed on PanelApp for Hereditary isolated diabetes insipidus (green, R440), Monogenic nephrogenic diabetes insipidus (green), and Renal tubulopathies (green, R198), indicating its clinical relevance in the UK for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the AVPR2 gene?
The AVPR2 gene provides instructions for the vasopressin V2 receptor, which is essential for regulating the body's water balance. It controls how much water the kidneys reabsorb from urine back into the bloodstream.
What health conditions are associated with AVPR2 gene variants?
Variants in the AVPR2 gene are primarily associated with Nephrogenic diabetes insipidus (X-linked). This condition causes the kidneys to be unable to respond to antidiuretic hormone, leading to excessive urination and thirst.
How is Nephrogenic diabetes insipidus inherited?
Nephrogenic diabetes insipidus caused by AVPR2 variants is inherited in an X-linked recessive pattern. This means it affects males more frequently and severely than females, as males have only one X chromosome.
References
- Bichet DG. Vasopressin receptor mutations in nephrogenic diabetes insipidus. Seminars in nephrology. 2008. PMID: 18519085
- Spanakis E, Milord E, Gragnoli C. AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. Journal of cellular physiology. 2008. PMID: 18726898
- Robben JH, Knoers NV, Deen PM. Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. American journal of physiology. Renal physiology. 2006. PMID: 16825342
- Rosenthal SM, Feldman BJ, Vargas GA. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD): a paradigm for activating mutations causing endocrine dysfunction. Pediatric endocrinology reviews : PER. 2006. PMID: 17261972
- Knoers NV. Hyperactive vasopressin receptors and disturbed water homeostasis. The New England journal of medicine. 2005. PMID: 15872199
- Feldman BJ, Rosenthal SM, Vargas GA. Nephrogenic syndrome of inappropriate antidiuresis. The New England journal of medicine. 2005. PMID: 15872203
- Arthus MF, Lonergan M, Crumley MJ. Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. Journal of the American Society of Nephrology : JASN. 2000. PMID: 10820168