PKD1
protein-codingpolycystin 1, transient receptor potential channel interacting, the group of MicroRNA protein coding host genes|C-type lectin domain containing
Gene summary
This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~47.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0004691
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008263
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009889
Submitter: ClinGen
*PKD1* was first reported in relation to biallelic polycystic kidney disease (PKD) in 2009 (Rossetti et al., PMID: 19165178). *PKD1* has been previously classified as definitive for autosomal dominant polycystic kidney disease (ADPKD). Biallelic disease of two fully pathogenic *PKD1* variants results in embryonic lethality and so viable biallelic cases must have at least one hypomorphic allele. This biallelic disease is a significant cause of very early onset PKD and can arise in a family with otherwise typical ADPKD (monoallelic family members). Individuals with a negative family history can have two hypomorphic alleles. At least seventeen unique variants (missense, nonsense, frameshift) that have been reported in thirteen probands in four publications (PMIDs: 19165178, 23624871, 30631912, 33168999) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (PMIDs: 26139440, 20558538). This gene-disease relationship is also supported by two mouse models, biochemical function data, and expression data (PMIDs: 9326937, 23064367, 11106764, 31427367, 8981910, 11891195). In summary, *PKD1* is definitively associated with autosomal recessive polycystic kidney disease (ARPKD-*PKD1*). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy GCEP on the meeting date 1/11/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0004691
Submitter: ClinGen
The PKD1 gene has been associated with autosomal dominant polycystic kidney disease in over 12 probands in 5 curated publications. PKD1 was first associated with this disease in humans in 1994 (The European Polycystic Kidney Disease Consortium). Variants in this gene segregate with disease and can occur de novo. The mechanism for disease is known to be loss of function. 125 unique variants (missense, in-frame indel, nonsense, frameshift, large deletion and complex rearrangements) have been classified as Pathogenic in ClinVar, 86 of which are frameshift, nonsense or canonical splice changes. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by ample experimental evidence including expression studies, biochemical function, protein interactions and animal models that recapitulate the human disease. In summary, PKD1 is definitively associated with autosomal dominant polycystic kidney disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Working Group on 5/22/2019 (SOP Version 6).
Inheritance Pattern: AD
Disease ID:MONDO:0010913
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008263
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0004691
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008263
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Gastrointestinal; Renal
Intervention: Cardiovascular; Gastrointestinal; Pharmacogenomic; Renal
Rationale: A number of manifestations can benefit from surveillance and early treatment, including surveillance for cardiovascular findings such as intracranial aneurysms and aortic dilation can allow early detection and treatment; Treatment for hypertension is frequently required (eg, with ACE inhibitors/angiotensin II receptor blockers); A number of agents should be avoided, including nephrotoxic agents, estrogens, smoking and agents that increase renal cysts; Additional considerations related to hepatic and other cyst-related manifestations may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PKD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001009944.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 5 | 132 | 891 | 19 | 1048 |
| missense | 30 | 331 | 3178 | 498 | 11 | 4048 |
| nonsense | 477 | 125 | 602 | |||
| start loss | 5 | 1 | 6 | |||
| frameshift | 1059 | 384 | 10 | 1453 | ||
| splice donor/acceptor (+/-2bp) | 134 | 136 | 11 | 281 | ||
| Total | 1706 | 981 | 3332 | 1389 | 30 | 7438 |
Highest pathogenic variant AF is 0.00032939846
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001009944.3 | 46 | MANE Select | |
| Ensembl | ENSP00000262304.4 | 46 | MANE Select | |
| RefSeq | NP_000287.4 | 46 | Standard | |
| Ensembl | ENSP00000399501.1 | 46 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pkd1a | Danio rerio | Structure: thoracic duct Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Polycystic Kidney Disease Pathway
- Simplified Interaction Map Between LOXL4 and Oxidative Stress Pathway
- GPR40 Pathway
- EMT transition in Colorectal Cancer
- VxPx cargo-targeting to cilium
Biological Process
- cartilage condensation
- in utero embryonic development
- kidney development
- liver development
- embryonic placenta development
Molecular Function
- calcium channel activity
- protein binding
- protein kinase binding
- protein domain specific binding
- carbohydrate binding
Cellular Component
- Golgi membrane
- polycystin complex
- nucleus
- cytoplasm
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262304
- Coding exons
- 46
- Length
- 47189
- Individuals with no LoFs
- 125394
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 34
- Defined
- 125428
- p
- 0.000136
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -4.32 | 3329 | 2.70e+3 | 1.23 | 0.000208 | 26961 |
| Missense (PolyPhen) | 745 | 793.89 | 0.93841 | 8642 | ||
| Synonymous | -17.9 | 2103 | 1.29e+3 | 1.63 | 0.000110 | 9531 |
| Loss of Function | 9.96 | 18 | 149 | 0.121 | 0.00000731 | 1597 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00050 | 0.00049 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00018 | 0.00013 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in renal tubulogenesis (PubMed:12482949). Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). Acts as a regulator of cilium length, together with PKD2 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling (By similarity). The cilium length response creates a negative feedback loop whereby fluid shear- mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). May be an ion-channel regulator. Involved in adhesive protein-protein and protein- carbohydrate interactions. {ECO:0000250|UniProtKB:O08852, ECO:0000269|PubMed:12482949}.;
- Disease
- DISEASE: Polycystic kidney disease 1 with or without polycystic liver disease (PKD1) [MIM:173900]: An autosomal dominant disorder characterized by renal cysts, liver cysts and intracranial aneurysm. Clinical variability is due to differences in the rate of loss of glomerular filtration, the age of reaching end-stage renal disease and the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial 'berry' aneurysm. {ECO:0000269|PubMed:10200984, ECO:0000269|PubMed:10364515, ECO:0000269|PubMed:10577909, ECO:0000269|PubMed:10647901, ECO:0000269|PubMed:10729710, ECO:0000269|PubMed:10854095, ECO:0000269|PubMed:10923040, ECO:0000269|PubMed:10987650, ECO:0000269|PubMed:11012875, ECO:0000269|PubMed:11058904, ECO:0000269|PubMed:11115377, ECO:0000269|PubMed:11216660, ECO:0000269|PubMed:11316854, ECO:0000269|PubMed:11558899, ECO:0000269|PubMed:11571556, ECO:0000269|PubMed:11691639, ECO:0000269|PubMed:11773467, ECO:0000269|PubMed:11857740, ECO:0000269|PubMed:11967008, ECO:0000269|PubMed:12007219, ECO:0000269|PubMed:12070253, ECO:0000269|PubMed:12220456, ECO:0000269|PubMed:12482949, ECO:0000269|PubMed:12842373, ECO:0000269|PubMed:15772804, ECO:0000269|PubMed:18837007, ECO:0000269|PubMed:21115670, ECO:0000269|PubMed:22508176, ECO:0000269|PubMed:8554072, ECO:0000269|PubMed:9199561, ECO:0000269|PubMed:9259200, ECO:0000269|PubMed:9285784, ECO:0000269|PubMed:9521593, ECO:0000269|PubMed:9921908}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.618
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |