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PKHD1
PKHD1 ciliary IPT domain containing fibrocystin/polyductin
The PKHD1 gene provides instructions for producing fibrocystin, a protein vital for proper kidney development and function, with implications for autosomal recessive polycystic kidney disease. PKHD1 encodes the fibrocystin protein, also known as polyductin, which is predominantly found in kidney cells, particularly within their primary cilia.
PKHD1 is located on the short (p) arm of chromosome 6, at band 6p12.3-p12.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The PKHD1 gene, short for Polycystic Kidney And Hepatic Disease 1, is essential for the normal development and maintenance of kidney structures. It provides the genetic blueprint for a protein named fibrocystin, also known as polyductin. This protein is found in foetal and adult kidney cells, and to a lesser extent in the liver and pancreas, where it contributes to cellular interactions and environmental responses.
Dysfunction of the PKHD1 gene is primarily linked to autosomal recessive polycystic kidney disease (ARPKD), a severe inherited disorder characterised by cyst formation in the kidneys and often in the liver. Understanding the gene's function is crucial for diagnosing and managing this condition.
What the gene does
The PKHD1 gene provides instructions for the production of fibrocystin, a large protein located in various cell types, with its most significant expression in kidney cells. Fibrocystin is situated within the cell membrane, allowing it to interact with molecules outside the cell and transmit signals into the cell's interior. This structural arrangement suggests a role in cellular communication, responding to external cues to regulate cellular processes.
Fibrocystin is also found in primary cilia, which are tiny, finger-like projections on the surface of cells, particularly those lining the renal tubules where urine is formed. These cilia are thought to be important for maintaining the structural integrity and size of these tubules. While its precise function within primary cilia is not fully understood, fibrocystin is believed to contribute to processes such as cell adhesion, repulsion, and cell proliferation. Its involvement in these fundamental cellular activities underscores its importance in kidney health and development.
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Chromosome location
The PKHD1 gene is located on the short arm of chromosome 6, specifically within the region designated 6p12.3-p12.2. This chromosomal address indicates its precise position within the human genome. Genes located in this region are part of a complex network contributing to various biological functions.
Protein structure
The fibrocystin protein, encoded by the PKHD1 gene, is exceptionally large, comprising 4074 amino acids. Its structure features multiple conserved domains. These include numerous IPT/TIG domains, specifically IPT/TIG 1; atypical (amino acids 24-111), IPT/TIG 2 (amino acids 137-232), IPT/TIG 3 (amino acids 259-335), IPT/TIG 4 (amino acids 931-1015), IPT/TIG 5 (amino acids 1019-1103), IPT/TIG 6; atypical (amino acids 1108-1192), IPT/TIG 7 (amino acids 1196-1289), IPT/TIG 8; atypical (amino acids 1301-1382), IPT/TIG 9 (amino acids 1389-1481), IPT/TIG 10 (amino acids 1486-1570), IPT/TIG 11 (amino acids 1573-1659), and IPT/TIG 12; atypical (amino acids 1658-1742). Additionally, the protein contains a PA14 domain (amino acids 322-485) and a G8 1 domain (amino acids 1932-2053), along with a PbH1 1 repeat (amino acids 2226-2248). These domains likely contribute to the protein's signalling and structural roles within cells.
Key variants
Variants within the PKHD1 gene can affect the production or function of the fibrocystin protein. These genetic changes can range from single DNA building block alterations to larger insertions or deletions. Given the critical role of fibrocystin in kidney development and function, pathogenic variants are associated with significant health consequences.
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.131delG | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10031T>G | p.Leu3344Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10109dup | p.Phe3371fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10126del | p.Ala3376fs | Pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10134G>A | p.Trp3378Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10136del | p.Thr3379fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10174C>T | p.Gln3392Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10219C>T | p.Gln3407Ter | Pathogenic | ★★☆☆ | not provided |
c.1032_1033del | p.Glu345fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
c.10334del | p.Asn3445fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive polycystic kidney disease |
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
Pathogenic variants in the PKHD1 gene are the primary cause of Autosomal recessive polycystic kidney disease (AR). This severe inherited disorder typically manifests at birth or in early infancy, characterised by the formation of numerous cysts in the kidneys, leading to impaired kidney function. It can also affect the liver, causing issues such as bile duct abnormalities and fibrosis.
Inheritance pattern
Conditions caused by pathogenic PKHD1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PKHD1 gene is actively assessed within the NHS Genomic Medicine Service, being listed on several PanelApp panels. These include Cholestasis, Cystic kidney disease, DDG2P, Ductal plate malformation, Foetal anomalies (R21), Neonatal cholestasis, Polycystic liver disease (R173), Rare multisystem ciliopathy disorders, Renal ciliopathies, and Unexplained kidney failure in young people. Its inclusion highlights its clinical significance in the diagnosis of these conditions within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the PKHD1 gene?
The PKHD1 gene provides instructions for the fibrocystin protein, which is important for the proper development and function of kidney cells. It plays a role in cell signalling, adhesion, and proliferation, particularly within primary cilia in the renal tubules.
Which condition is most commonly associated with PKHD1 gene variants?
Variants in the PKHD1 gene are predominantly associated with Autosomal recessive polycystic kidney disease (AR). This condition leads to the development of cysts in the kidneys and can also affect the liver.
How is Autosomal recessive polycystic kidney disease (ARPKD) inherited?
ARPKD is inherited in an autosomal recessive manner. This means that an individual must inherit two copies of a pathogenic PKHD1 variant, one from each parent, to develop the condition. Individuals with only one pathogenic variant are typically carriers and do not show symptoms.
References
- Bergmann C, Senderek J, Windelen E. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney international. 2005. PMID: 15698423
- Sharp AM, Messiaen LM, Page G. Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. Journal of medical genetics. 2005. PMID: 15805161
- Wilson PD. Polycystic kidney disease. The New England journal of medicine. 2004. PMID: 14711914
- Harris PC, Rossetti S. Molecular genetics of autosomal recessive polycystic kidney disease. Molecular genetics and metabolism. 2004. PMID: 14741187
- Lina F, Satlinb LM. Polycystic kidney disease: the cilium as a common pathway in cystogenesis. Current opinion in pediatrics. 2004. PMID: 15021197
- Bergmann C, Senderek J, Küpper F. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Human mutation. 2004. PMID: 15108277
- Ward CJ, Yuan D, Masyuk TV. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Human molecular genetics. 2003. PMID: 12925574
- Ward CJ, Hogan MC, Rossetti S. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nature genetics. 2002. PMID: 11919560
- Adam MP, Bick S, Mirzaa GM. Autosomal Recessive Polycystic Kidney Disease – PKHD1. 1993. PMID: 20301501