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PKHD1
PKHD1 ciliary IPT domain containing fibrocystin/polyductin
The PKHD1 gene encodes the fibrocystin protein, which is essential for normal kidney development and function, with pathogenic variants linked to autosomal recessive polycystic kidney disease (ARPKD). PKHD1 provides the genetic blueprint for fibrocystin, a protein predominantly found in kidney cells.
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, also known as fibrocystin or polyductin, plays a critical role in human kidney development and function. It provides instructions for producing the fibrocystin protein, which is found in both foetal and adult kidney cells, and to a lesser extent in the liver and pancreas. The proper functioning of PKHD1 is vital for maintaining the structure of renal tubules, the small tubes in the kidneys where urine is formed.
What the gene does
The fibrocystin protein, encoded by the PKHD1 gene, is located within cell membranes of kidney cells, with part of the protein extending inside and part projecting outside the cell. Its structure suggests it may act as a receptor, receiving signals from the cellular environment. Fibrocystin is thought to be involved in various cellular processes, including cell adhesion, repulsion, and proliferation, which are important for tissue organisation and growth. It is also found in primary cilia, tiny finger-like projections on cells lining renal tubules, where it is believed to contribute to the maintenance of tubule size and structure, though its precise role in cilia is still being researched.
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Chromosome location
The PKHD1 gene is situated on the short arm of chromosome 6, specifically within the region designated 6p12.3-p12.2. This genomic location is consistent across the human population.
Protein structure
The fibrocystin protein is a large protein, consisting of 4074 amino acids. Its structure features multiple IPT/TIG domains, including IPT/TIG 1 (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 (amino acids 1108-1192), IPT/TIG 7 (amino acids 1196-1289), IPT/TIG 8 (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 (amino acids 1658-1742). Other notable domains include 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).
Key variants
Variants within the PKHD1 gene can affect the production or function of the fibrocystin protein. Over 270 different types of pathogenic variants have been identified, including single base-pair changes, as well as insertions or deletions of small numbers of DNA building blocks. These genetic changes can lead to a dysfunctional protein, impairing its ability to perform its crucial roles in kidney development and maintenance.
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 (ARPKD). This is a severe form of polycystic kidney disease that typically manifests at birth or in early infancy. ARPKD is characterised by the development of numerous cysts in the kidneys and, in some cases, the liver, which can lead to significant organ dysfunction.
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 included in several NHS England Genomic Medicine Service national panels. These include panels for Cholestasis (R171), 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.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main condition associated with the PKHD1 gene?
The primary condition linked to pathogenic variants in the PKHD1 gene is Autosomal recessive polycystic kidney disease (ARPKD), a severe kidney disorder typically appearing in infancy.
How is PKHD1 inherited?
PKHD1 is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic variant (one from each parent) to develop the associated condition.
What does the fibrocystin protein do?
The fibrocystin protein, encoded by PKHD1, is crucial for kidney cell function and development. It is involved in cell signalling, adhesion, and maintaining the structure of renal tubules within the kidneys.
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