On this page
PKD1
polycystin 1, transient receptor potential channel interacting
The *PKD1* gene provides instructions for making polycystin-1, a protein crucial for normal kidney development and function, with pathogenic variants causing Autosomal Dominant Polycystic Kidney Disease. The *PKD1* gene encodes the polycystin-1 protein, a transmembrane protein extensively involved in cellular signalling and interactions within the kidneys.
PKD1 is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The *PKD1* gene, formally known as polycystin 1, transient receptor potential channel interacting, is fundamental to cellular processes within the kidney. It provides the genetic blueprint for creating polycystin-1, a complex protein active in kidney cells, particularly during foetal development, though its exact mechanisms are still being elucidated [PMID:17949929].
Polycystin-1 works in conjunction with polycystin-2, a related protein, to regulate vital cellular activities including growth, division, migration, and intercellular communication [PMID:17006856]. These functions are critical for maintaining the structural integrity and proper functioning of the kidneys, with disruptions leading to significant health implications, particularly Autosomal Dominant Polycystic Kidney Disease. Research suggests that the protein's activity is highest before birth, with substantially reduced expression observed in healthy mature kidneys [PMID:17949929].
What the gene does
The polycystin-1 protein, encoded by the *PKD1* gene, is instrumental in various cellular signalling pathways, particularly within kidney cells. This protein is a transmembrane receptor, meaning it spans the cell membrane, allowing one part to interact with the extracellular environment and another part to signal inside the cell [PMID:17006856]. It binds to external molecules such as other proteins, carbohydrates, and lipids, enabling a cell to react to its surroundings.
When an extracellular molecule attaches to polycystin-1, this protein works together with polycystin-2 to set off a series of biochemical signals within the cell. These internal signals direct the cell through developmental changes, including maturation into specialised forms. Evidence suggests that the two polycystins coordinate the regulation of how cells multiply, relocate, and communicate with neighbouring cells. Polycystin-1 is also present in primary cilia, small, hair-like projections on the surface of renal tubule cells, where urine forms. These cilia are thought to sense fluid movement, which helps maintain the size and structure of the tubules, promoting normal kidney development and function through the polycystin interaction.
Video: Genetics 101
Chromosome location
The *PKD1* gene is located on the short arm of chromosome 16, specifically at band 16p13.3. This precise location within the human genome places *PKD1* in an area of significant genetic activity. The gene encodes a large protein comprising 4303 amino acids, reflecting its complex structure and diverse functional roles within the cell.
Protein structure
The polycystin-1 protein is a large, complex molecule with several distinct functional regions and domains [PMID:17006856]. At its N-terminus, it features a Leucine-rich repeat N-terminal (LRRNT) domain (amino acids 24-67), followed by two Leucine-rich repeats: LRR 1 (amino acids 68-91) and LRR 2 (amino acids 92-113). Directly downstream is the LRRCT domain (amino acids 125-178), and a WSC domain (amino acids 177-271).
Further into the polypeptide chain, two PKD domains, PKD 1 (amino acids 272-359) and PKD 2 (amino acids 743-817), are present. A C-type lectin domain is located between amino acids 415-531, playing a role in carbohydrate binding. Additionally, an LDL-receptor class A; atypical domain (amino acids 638-671) is identified. The protein also contains multiple other PKD domains, including PKD 3 (amino acids 855-928), PKD 4 (amino acids 935-1020), PKD 5 (amino acids 1023-1129), PKD 6 (amino acids 1127-1215), PKD 7 (amino acids 1213-1298), and continuing through PKD 12 (amino acids 1634-1721). A disordered region is also noted between amino acids 616-635, indicating a segment without a fixed three-dimensional structure.
Key variants
Genetic variants in the *PKD1* gene can significantly alter its function, leading to pathogenic effects. These changes can include single nucleotide polymorphisms (SNPs), small deletions, or insertions within the gene sequence. Each type of variant can impact the production or function of the polycystin-1 protein, typically resulting in a reduced or non-functional protein. Understanding the specific nature of these variants is crucial for elucidating their clinical consequences, particularly in relation to inherited kidney disorders.
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.4375C>T | p.Arg1459Ter | Pathogenic | ★★☆☆ | Tuberous sclerosis syndrome |
c.10084C>T | p.Gln3362Ter | Pathogenic | ★★☆☆ | not provided |
c.10087C>T | p.Gln3363Ter | Pathogenic | ★★☆☆ | Polycystic kidney disease, adult type |
c.10118C>A | p.Ser3373Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Polycystic kidney disease, adult type |
c.10167+25_10167+43del | - | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.10168C>T | p.Gln3390Ter | Pathogenic | ★★☆☆ | Polycystic kidney disease, adult type |
c.10183C>T | p.Gln3395Ter | Pathogenic | ★★☆☆ | Polycystic kidney disease, adult type |
c.1021dup | p.Ala341fs | Pathogenic | ★★☆☆ | PKD1-related disorder |
c.10233del | p.Trp3411fs | Pathogenic | ★★☆☆ | not provided |
c.10259G>A | p.Trp3420Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
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 *PKD1* gene are predominantly associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD), a condition characterised by developing numerous fluid-filled cysts within the kidneys, which can impair renal function over time. More than 250 distinct genetic alterations have been identified within the *PKD1* gene that cause polycystic kidney disease. These variants are responsible for approximately 85% of Autosomal Dominant Polycystic Kidney Disease cases, establishing *PKD1* as the primary genetic cause of this disorder [PMID:17949929].
Inheritance pattern
Conditions caused by pathogenic PKD1 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 *PKD1* gene is included in several NHS England Genomic Medicine Service national genomic test directories, reflecting its clinical significance. It is part of panels for Cystic kidney disease, Ductal plate malformation, and Renal ciliopathies. Furthermore, *PKD1* is also assessed in the Foetal anomalies (R21), Polycystic liver disease (R173), and Unexplained kidney failure in young people panels, indicating its broad impact on renal and other related conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research into lifestyle factors for individuals with conditions linked to *PKD1* variants, such as Autosomal Dominant Polycystic Kidney Disease, suggests that certain choices may support overall renal health. Maintaining a balanced diet, including adequate hydration, and managing blood pressure are often recommended for general kidney wellness. Regular, moderate physical activity, where appropriate, may also contribute to general health. It is important for individuals to discuss any lifestyle changes with their healthcare provider.
Supplement considerations
Currently, there is no conclusive scientific evidence that specific dietary supplements can prevent conditions caused by *PKD1* gene variants. While some research explores the potential benefits of various compounds, these studies are generally in early stages and have not yielded definitive clinical recommendations. Individuals considering any supplements should consult with their general practitioner or a registered dietitian, particularly due to potential interactions with medications or underlying health conditions.
Frequently asked questions
What is the primary function of the *PKD1* gene?
The *PKD1* gene provides instructions for making the polycystin-1 protein, which is essential for normal kidney development and function by regulating cell growth, division, and interactions, often in conjunction with polycystin-2.
Which condition is most commonly associated with *PKD1* variants?
Variants in the *PKD1* gene are most commonly associated with Autosomal Dominant Polycystic Kidney Disease, a condition characterised by the growth of numerous cysts in the kidneys.
How does polycystin-1 contribute to kidney health?
Polycystin-1, found in kidney cell membranes and primary cilia, helps cells respond to their environment and regulates crucial processes like cell growth and fluid sensing in renal tubules, which are vital for maintaining kidney structure and function.
Is *PKD1* included in any UK genetic testing panels?
Yes, *PKD1* is included in several NHS England Genomic Medicine Service national genomic test directories, such as those for Cystic kidney disease, Renal ciliopathies, and Foetal anomalies.
Can lifestyle changes influence conditions related to *PKD1*?
While lifestyle changes cannot alter the genetic cause of conditions linked to *PKD1*, maintaining a healthy diet, adequate hydration, and blood pressure management may support overall kidney health. Any lifestyle adjustments should be discussed with a healthcare provider.
References
- Nauli SM, Rossetti S, Kolb RJ. Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. Journal of the American Society of Nephrology : JASN. 2006. PMID: 16565258
- 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
- Horie S. ADPKD: molecular characterization and quest for treatment. Clinical and experimental nephrology. 2005. PMID: 16362154
- 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