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PKD2
polycystin 2, transient receptor potential cation channel
The PKD2 gene provides instructions for making polycystin-2, a protein vital for kidney development and function, particularly through its role as an ion channel. PKD2 encodes polycystin-2, a protein found in various tissues, including the kidneys.
PKD2 is located on the long (q) arm of chromosome 4, at band 4q22.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PKD2 gene instructs the creation of the polycystin-2 protein. This protein is widely present in many tissues, including the kidneys, even before birth. Polycystin-2 plays a critical role in cellular signalling by forming an ion channel, which is essential for normal kidney development and maintaining tubular structures.
Dysfunction of the PKD2 gene is primarily associated with inherited kidney disorders, particularly autosomal dominant polycystic kidney disease (ADPKD), a condition characterised by the development of numerous fluid-filled cysts in the kidneys. Understanding the normal function of PKD2 and the impact of its variants is crucial for comprehending the progression of such conditions.
What the gene does
The polycystin-2 protein, encoded by the PKD2 gene, primarily functions as a calcium-permeable transient receptor potential (TRP) cation channel [PMID:16099513]. This channel is integral to the cell membrane, facilitating the movement of positively charged ions, particularly calcium, into the cell. This calcium influx can initiate a cascade of biochemical reactions within the cell, influencing various cellular activities [PMID:16099513].
Polycystin-2 often collaborates with polycystin-1, a larger, structurally similar protein. Together, they are thought to regulate fundamental cellular processes, including cell growth, division (proliferation), movement (migration), and interactions between cells [PMID:16099513]. These functions are especially important for the development and healthy maintenance of kidney structures.
Beyond the cell membrane, polycystin-2 is also active in primary cilia, which are small, finger-like projections found on cells lining renal tubules-the tiny tubes within the kidneys where urine is formed. Researchers propose that primary cilia, with the involvement of polycystin-2, sense fluid flow through these tubules. This sensing mechanism is believed to help maintain the appropriate size and structure of the renal tubules, highlighting polycystin-2's broader importance in kidney development and function.
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Chromosome location
The PKD2 gene is situated on the long arm of chromosome 4, specifically at position 4q22.1. This precise genomic location helps in mapping and understanding its role in inherited conditions. The gene provides instructions for a protein that is 968 amino acids in length.
Protein structure
The polycystin-2 protein, encoded by the PKD2 gene, consists of 968 amino acids and exhibits a complex domain architecture essential for its function as an ion channel. Several regions are identified as Disordered, spanning amino acids 1-28, 58-181, 764-831, and 917-968. A crucial Selectivity filter motif is located between amino acids 641-643, which is key for ion permeation. An EF-hand domain, positioned from amino acids 750-785, is typically involved in calcium binding. A Linker region is found from amino acids 803-822, with a specific segment within this region (amino acids 810-821) being important for interaction with PACS1 and PACS2 proteins. Finally, a Coiled coil region from amino acids 833-872 is present, often facilitating protein-protein interactions.
Key variants
Variants within the PKD2 gene can alter the structure or function of the polycystin-2 protein, leading to various health implications. Research has documented more than 75 pathogenic changes in the PKD2 gene among individuals with polycystic kidney disease. These variants can include small changes in single DNA building blocks or larger alterations like deletions or insertions of DNA segments. The precise nature and location of a variant can influence the severity and presentation of associated medical conditions.
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.1018G>T | p.Glu340Ter | Pathogenic | ★★☆☆ | Autosomal dominant polycystic kidney disease |
c.1039del | p.Val347fs | Pathogenic | ★★☆☆ | not provided |
c.1040del | p.Val347fs | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease 2 |
c.1047dup | p.Val350fs | Pathogenic | ★★☆☆ | Polycystic kidney disease 2 |
c.1081C>T | p.Arg361Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1087G>T | p.Gly363Ter | Pathogenic | ★★☆☆ | not provided |
c.1094+1G>A | - | Pathogenic | ★★☆☆ | not provided |
c.1094+1G>C | - | Pathogenic | ★★☆☆ | Polycystic kidney disease |
c.1094+3_1094+6del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease |
c.110del | p.Gly37fs | Pathogenic | ★★☆☆ | Polycystic kidney disease 2 |
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 PKD2 gene are a known genetic cause of Autosomal dominant polycystic kidney disease (ADPKD). This condition is the most common inherited kidney disorder, characterised by the development of numerous cysts in the kidneys, which can progressively impair kidney function. PKD2 variants are responsible for about 15% of all ADPKD cases. Understanding the genetic basis of this condition is important for diagnosis and management.
Inheritance pattern
Conditions caused by pathogenic PKD2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the PKD2 gene is recognised on several NHS Genomic Medicine Service clinical panels, indicating its importance in diagnostic genetics. It is listed as 'green' on panels for Cystic kidney disease, Ductal plate malformation, Polycystic liver disease, Rare multisystem ciliopathy disorders, Renal ciliopathies, and Unexplained kidney failure in young people. Additionally, it is included on panels for Foetal anomalies (R21) and Paediatric or syndromic cardiomyopathy (R135).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
For individuals with PKD2-related conditions, general health recommendations often support kidney health. Maintaining a healthy lifestyle, including a balanced diet and regular physical activity, is broadly beneficial for the general population. It is always recommended to discuss any specific lifestyle changes with a healthcare provider to ensure they are appropriate for individual circumstances.
Supplement considerations
There is no conclusive evidence that specific dietary supplements can prevent or cure conditions associated with the PKD2 gene. While some supplements are marketed for kidney health, their efficacy and safety for individuals with PKD2-related conditions are not well-established. Before taking any supplements, it is important to consult with a healthcare professional to ensure they are safe and do not interact negatively with any existing medical conditions or treatments.
Frequently asked questions
What is the primary function of the PKD2 gene?
The PKD2 gene provides instructions for the polycystin-2 protein, which primarily functions as a transient receptor potential (TRP) cation channel. This channel regulates the flow of calcium ions into cells, influencing cell growth, division, and other cellular processes.
What conditions are associated with variants in the PKD2 gene?
Variants in the PKD2 gene are a known cause of Autosomal dominant polycystic kidney disease (ADPKD). This condition leads to the development of numerous fluid-filled cysts in the kidneys, which can impair kidney function over time.
Where is the PKD2 gene located?
The PKD2 gene is located on chromosome 4, specifically at band 4q22.1. This position helps in mapping its genetic location within the human genome.
How common are PKD2 variants in ADPKD?
Variants in the PKD2 gene are responsible for approximately 15% of all cases of autosomal dominant polycystic kidney disease (ADPKD), making it a significant genetic factor for this condition.
Are there other names for the PKD2 gene?
Other names for the PKD2 gene include polycystin 2, transient receptor potential cation channel, which reflects its full name and function.
References
- Grimm DH, Karihaloo A, Cai Y. Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells. The Journal of biological chemistry. 2006. PMID: 16278216
- Bissler JJ, Dixon BP. A mechanistic approach to inherited polycystic kidney disease. Pediatric nephrology (Berlin, Germany). 2005. PMID: 15719257
- Ong AC, Harris PC. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney international. 2005. PMID: 15780076
- Al-Bhalal L, Akhtar M. Molecular basis of autosomal dominant polycystic kidney disease. Advances in anatomic pathology. 2005. PMID: 15900113
- Wilson PD. Polycystic kidney disease. The New England journal of medicine. 2004. PMID: 14711914
- Boucher C, Sandford R. Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). European journal of human genetics : EJHG. 2004. PMID: 14872199
- Lina F, Satlinb LM. Polycystic kidney disease: the cilium as a common pathway in cystogenesis. Current opinion in pediatrics. 2004. PMID: 15021197
- Nauli SM, Alenghat FJ, Luo Y. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature genetics. 2003. PMID: 12514735
- Adam MP, Bick S, Mirzaa GM. Polycystic Kidney Disease, Autosomal Dominant. 1993. PMID: 20301424