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PKD1 (polycystic kidney disease 1 (autosomal dominant))

Written2011-07Ying-Cai Tan, Hanna Rennert
Department of Pathology, Laboratory Medicine, Weill Cornell Medical College 1300 York Street, F701 New York, NY 10065, USA

(Note : for Links provided by Atlas : click)

Identity

Other namesPBP
Pc-1
polycystin-1
TRPP1
HGNC (Hugo) PKD1
LocusID (NCBI) 5310
Atlas_Id 41725
Location 16p13.3  [Link to chromosome band 16p13]
Location_base_pair Starts at 2138711 and ends at 2185899 bp from pter ( according to hg19-Feb_2009)  [Mapping PKD1.png]
 
  Ideogram of human chromosome 16, the location of PKD1 gene is indicated by the red vertical line. This graph was generated by using UCSC genome browser.
Fusion genes
(updated 2016)
PKD1 (16p13.3) / SLIT1 (10q24.1)UBE2J2 (1p36.33) / PKD1 (16p13.3)

DNA/RNA

 
  Gene structure of PKD1, showing the intron/exon structure. Exons are shown with solid box; introns are shown with thin line arrow heads; 3' and 5' UTR regions are indicated by open boxes. Some exons numbers are labelled above. This graph was generated by using UCSC genome browser.
Description This gene has 46 exons that span ~52 kb of genomic sequence. Exons 1-33 are located in a genomic region which is duplicated six times on the same chromosome (~13-16 Mb proximal to PKD1 on the short arm of chromosome 16), resulting in six pseudogenes. A Mirtron family microRNA gene, miR-1225, is lying within intron 45 of PKD1, the function of this microRNA is currently unknown.
Transcription The 14,5 kb transcript has two different isoforms as a result of alternative splicing. The longer variant, isoform I (NM_001009944), has a 12909 bp open reading frame. The short variant, isoform II (NM_000293), uses an alternate acceptor splice site, 3 nt downstream of that used by isoform I, at the junction of intron 31 and exon 32. This results in an isoform (variant II) that is one amino acid shorter than isoform I.
Pseudogene The six pseudogenes that result from duplication of PKD1 exon 1 through 33 are located on chromosome 16p13.1 and have 97-99% identity to PKD1. Those pseudogenes are transcripted into mRNA species with suboptimal start codons, thus they are not translated.

Protein

 
  Protein structure of polycystin-1 (PC1). The details of the protein domain structures are shown. Abreviation: GPS, GPCR Proteolystic Site; WSC, cell Wall integrity and Stress response Component; PLAT, (Polycystin-1, Lipoxygenase, Alpha-Toxin); REJ, Receptor for Egg Jelly. This graph was generated by using ExPASY Proteomics Server PROSITE module with some modifications.
Description The longer form of polycystin-1, isoform I, has 4303 aa. It is a 460 kDa membrane protein which has the structure of a receptor or adhesion molecule. The large extracellular N-terminal region consisting of a variety of domains, including 12 PKD domains (an immunoglobin-like fold), two leucine-rich repeats, C-type lectin domain, WSC domain, GPS domain and REJ domain. The short intracellular C-terminal region has 197 aa, containing a coiled-coil domain that interact with polycystin-2 and a G-protein binding domain. Between the N and C-terminal is a large transmembrane region (1032 aa) that has 11 transmembrane domains. Polycystin-1 is cleaved at the G protein-coupled receptor proteolytic site (GPS) domain, resulting in a 150 kDa C-terminal fragment and a 400 kDa N-terminal fragment that tether to the membrane. This cleavage is suggested to be important for protein activation.
Expression Polycystin-1 is widely expressed in adult tissue, with high levels in brain and moderate expression in kidney. In fetal and adult kidney, the expression was restricted to the epithelial cells with highest expression in the embryo and downregulation in adult. In smooth, skeletal and cardiac muscles, expression is also found.
Localisation Polycystin-1 is located in the primary cilium, a single hair-like organelle projecting from the surface of most mammalian cells. It is also found in the plasma membrane at focal adhesions, desmosomes, and adherens junctions. The C-terminal tail of PC1 has been reported to be cleaved and migrate to the nucleus, regulating gene expression.
Function In the kidney tubule, polycystin-1 was shown to serve as a mechanoreceptor that senses fluid flow in the tubular lumen, triggering Ca2+ influx through polycystin-2, a Ca2+ channel that interact with PC1 in the C-terminal tail, consequently affecting the intracellular calcium and cyclic AMP (cAMP) levels. It is also involved in cell-to-cell or cell-to-matrix interactions.
Homology The characterized domains of polycystin-1 are regions highly conserved among species (from human to fish). A homology and also an interaction partner in the same signaling passway, polycystin-2, is located on 4q21.

Mutations

Germinal Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Up to 85% of ADPKD cases are caused by mutations in PKD1 gene. With the current mutation detection methods, definite pathogenic mutations (nonsense, truncation and canonical splice defects) are identified in approximately 60% of the cases. Large deletions/insertions can be found in ~4% of cases. Comprehensive analyses, using bioinformatics analysis tools can identify missense mutations that may account for the disease in an additional 22% to 37% of the ADPKD patients. There are no mutation hot spots for PKD1, which means mutations are usually private, with 70% of the mutations unique to a single family, and spread throughout the entire gene. Mutations on 5' of the gene are associated with a more sever disease compared to those occurring in 3' region. The ADPKD Mutation Database at Mayo Clinic (http://pkdb.mayo.edu/), the most complete one for ADPKD, documents 416 pathogenic mutations for PKD1 in a total of 616 families.
Somatic The pathogenesis of ADPKD has been attributed to a two-hit mechanism, with somatic and germline mutations combining to inactivate one of the PKD genes, leading to loss of function, thus initiating the disease process. There are significantly less somatic PKD mutations listed in the ADPKD Mutation Database, only 9 for PKD1 (http://pkdb.mayo.edu/). Due to the limited availability of kidney cyst DNA and the complications associated with PKD1 genotyping, analyzing somatic mutations in ADPKD was proven to be difficult.

Implicated in

Note
Entity Autosomal dominant polycystic kidney disease (ADPKD)
Disease ADPKD is a monogenic multi-systemic disorder characterized by age-dependent development and progressive enlargement of bilateral, multiple renal cysts, resulting in chronic renal failure typically in mid to late adulthood. The cysts are caused by abnormal proliferation of renal tubule epithelial cells as a result of inactivation of the PKD genes by mutations. Mutations in PKD1 gene account for 85% of the ADPKD cases and for the early-onset, more sever form. Those cysts will increase gradually in both size and number, leading to massive kidney enlargement and progressive decline in renal function. ADPKD has a prevalence of approximately 1 in 400 to 1 in 1000 live births in all races, affecting approximately 12,5 million individuals worldwide. Although ADPKD accounts for 4,4% of all patients requiring renal replacement therapy, it is characterized by very large phenotypic variability, ranging from presentation in-utero with enlarged, cystic kidneys to incidental diagnosis in the elderly with adequate renal function. Extra-renal manifestations include cysts in the liver, pancreas, seminal vesicles and arachnoid membranes. Intracranial aneurysm is about five times more common than in the general population and is associated with significant morbidity and mortality.
Prognosis About 50% of patients with ADPKD will progress to end stage renal disease (ESRD) by the age of 60 years, with hemodialysis or kidney transplant being the only currently available treatment, though several potential drugs have been entered into clinical trials. Hypertension is present in about 50% of ADPKD patients age 20-30 years with clinically normal renal function; this is approximately one decade earlier than the onset of primary hypertension in the general population.
  

Bibliography

Polycystic kidney disease.
Wilson PD.
N Engl J Med. 2004 Jan 8;350(2):151-64. (REVIEW)
PMID 14711914
 
Autosomal dominant polycystic kidney disease.
Torres VE, Harris PC, Pirson Y.
Lancet. 2007 Apr 14;369(9569):1287-301. (REVIEW)
PMID 17434405
 
Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease.
Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R, Balina M, Parker T, Levine D, Leonard DG, Rennert H.
Hum Mutat. 2009 Feb;30(2):264-73.
PMID 18837007
 
Autosomal dominant polycystic kidney disease: the last 3 years.
Torres VE, Harris PC.
Kidney Int. 2009 Jul;76(2):149-68. Epub 2009 May 20. (REVIEW)
PMID 19455193
 
Molecular diagnostics for autosomal dominant polycystic kidney disease.
Harris PC, Rossetti S.
Nat Rev Nephrol. 2010 Apr;6(4):197-206. Epub 2010 Feb 23. (REVIEW)
PMID 20177400
 

Citation

This paper should be referenced as such :
Tan, YC ; Rennert, H
PKD1 (polycystic kidney disease 1 (autosomal dominant))
Atlas Genet Cytogenet Oncol Haematol. 2012;16(1):22-24.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PKD1ID41725ch16p13.html


External links

Nomenclature
HGNC (Hugo)PKD1   9008
Cards
AtlasPKD1ID41725ch16p13
Entrez_Gene (NCBI)PKD1  5310  polycystin 1, transient receptor potential channel interacting
AliasesPBP; Pc-1; TRPP1
GeneCards (Weizmann)PKD1
Ensembl hg19 (Hinxton)ENSG00000008710 [Gene_View]  chr16:2138711-2185899 [Contig_View]  PKD1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000008710 [Gene_View]  chr16:2138711-2185899 [Contig_View]  PKD1 [Vega]
ICGC DataPortalENSG00000008710
TCGA cBioPortalPKD1
AceView (NCBI)PKD1
Genatlas (Paris)PKD1
WikiGenes5310
SOURCE (Princeton)PKD1
Genomic and cartography
GoldenPath hg19 (UCSC)PKD1  -     chr16:2138711-2185899 -  16p13.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PKD1  -     16p13.3   [Description]    (hg38-Dec_2013)
EnsemblPKD1 - 16p13.3 [CytoView hg19]  PKD1 - 16p13.3 [CytoView hg38]
Mapping of homologs : NCBIPKD1 [Mapview hg19]  PKD1 [Mapview hg38]
OMIM173900   601313   
Gene and transcription
Genbank (Entrez)AB209025 AB209675 AK309422 CN268814 L33243
RefSeq transcript (Entrez)NM_000296 NM_001009944
RefSeq genomic (Entrez)NC_000016 NC_018927 NG_008617 NT_010393 NW_004929400
Consensus coding sequences : CCDS (NCBI)PKD1
Cluster EST : UnigeneHs.75813 [ NCBI ]
CGAP (NCI)Hs.75813
Alternative Splicing GalleryENSG00000008710
Gene ExpressionPKD1 [ NCBI-GEO ]   PKD1 [ EBI - ARRAY_EXPRESS ]   PKD1 [ SEEK ]   PKD1 [ MEM ]
Gene Expression Viewer (FireBrowse)PKD1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5310
GTEX Portal (Tissue expression)PKD1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP98161 (Uniprot)
NextProtP98161  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP98161
Splice isoforms : SwissVarP98161 (Swissvar)
PhosPhoSitePlusP98161
Domaine pattern : Prosite (Expaxy)C_TYPE_LECTIN_2 (PS50041)    GPS (PS50221)    LRR (PS51450)    PKD (PS50093)    PLAT (PS50095)    REJ (PS51111)    WSC (PS51212)   
Domains : Interpro (EBI)C-type_lectin    C-type_lectin-like    C-type_lectin_fold    Cys-rich_flank_reg_C    GPS    L_dom-like    Leu-rich_rpt    Leu-rich_rpt_typical-subtyp    LRRNT    PC1    PKD/Chitinase_dom    PKD/REJ-like    PKD1_2_channel    PKD_dom    PLAT/LH2_dom    Polycystin_cat    REJ_dom    WSC_carb-bd    WSC_carb-bd_subgr   
Domain families : Pfam (Sanger)Lectin_C (PF00059)    LRR_8 (PF13855)    PKD (PF00801)    PKD_channel (PF08016)    PLAT (PF01477)    REJ (PF02010)    WSC (PF01822)   
Domain families : Pfam (NCBI)pfam00059    pfam13855    pfam00801    pfam08016    pfam01477    pfam02010    pfam01822   
Domain families : Smart (EMBL)CLECT (SM00034)  GPS (SM00303)  LH2 (SM00308)  LRR_TYP (SM00369)  LRRCT (SM00082)  LRRNT (SM00013)  PKD (SM00089)  WSC (SM00321)  
DMDM Disease mutations5310
Blocks (Seattle)PKD1
PDB (SRS)1B4R   
PDB (PDBSum)1B4R   
PDB (IMB)1B4R   
PDB (RSDB)1B4R   
Structural Biology KnowledgeBase1B4R   
SCOP (Structural Classification of Proteins)1B4R   
CATH (Classification of proteins structures)1B4R   
SuperfamilyP98161
Human Protein AtlasENSG00000008710
Peptide AtlasP98161
HPRD03203
IPIIPI00409566   IPI00409567   IPI00028786   IPI00956538   IPI00556317   IPI00883708   
Protein Interaction databases
DIP (DOE-UCLA)P98161
IntAct (EBI)P98161
FunCoupENSG00000008710
BioGRIDPKD1
STRING (EMBL)PKD1
ZODIACPKD1
Ontologies - Pathways
QuickGOP98161
Ontology : AmiGOGolgi membrane  cartilage condensation  in utero embryonic development  kidney development  liver development  embryonic placenta development  polycystin complex  calcium channel activity  calcium channel activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  integral component of plasma membrane  cilium  protein export from nucleus  nitrogen compound metabolic process  cell cycle arrest  homophilic cell adhesion via plasma membrane adhesion molecules  cell-matrix adhesion  calcium-independent cell-matrix adhesion  positive regulation of cytosolic calcium ion concentration  JAK-STAT cascade  heart development  anatomical structure morphogenesis  cell surface  integral component of membrane  basolateral plasma membrane  lateral plasma membrane  single organismal cell-cell adhesion  peptidyl-serine phosphorylation  protein kinase binding  protein domain specific binding  spinal cord development  neural tube development  establishment of cell polarity  regulation of cell adhesion  carbohydrate binding  Golgi-associated vesicle membrane  motile primary cilium  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  positive regulation of protein binding  response to fluid shear stress  lymph vessel morphogenesis  cytoplasmic sequestering of transcription factor  skin development  ion channel binding  positive regulation of transcription from RNA polymerase II promoter  digestive tract development  branching morphogenesis of an epithelial tube  genitalia development  detection of mechanical stimulus  detection of mechanical stimulus  cartilage development  ciliary membrane  regulation of mitotic spindle organization  lung epithelium development  placenta blood vessel development  regulation of proteasomal protein catabolic process  extracellular exosome  calcium ion transmembrane transport  mesonephric tubule development  mesonephric duct development  metanephric collecting duct development  metanephric ascending thin limb development  metanephric proximal tubule development  metanephric distal tubule morphogenesis  primary cilium  
Ontology : EGO-EBIGolgi membrane  cartilage condensation  in utero embryonic development  kidney development  liver development  embryonic placenta development  polycystin complex  calcium channel activity  calcium channel activity  protein binding  nucleus  cytoplasm  cytosol  plasma membrane  integral component of plasma membrane  cilium  protein export from nucleus  nitrogen compound metabolic process  cell cycle arrest  homophilic cell adhesion via plasma membrane adhesion molecules  cell-matrix adhesion  calcium-independent cell-matrix adhesion  positive regulation of cytosolic calcium ion concentration  JAK-STAT cascade  heart development  anatomical structure morphogenesis  cell surface  integral component of membrane  basolateral plasma membrane  lateral plasma membrane  single organismal cell-cell adhesion  peptidyl-serine phosphorylation  protein kinase binding  protein domain specific binding  spinal cord development  neural tube development  establishment of cell polarity  regulation of cell adhesion  carbohydrate binding  Golgi-associated vesicle membrane  motile primary cilium  positive regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle  positive regulation of protein binding  response to fluid shear stress  lymph vessel morphogenesis  cytoplasmic sequestering of transcription factor  skin development  ion channel binding  positive regulation of transcription from RNA polymerase II promoter  digestive tract development  branching morphogenesis of an epithelial tube  genitalia development  detection of mechanical stimulus  detection of mechanical stimulus  cartilage development  ciliary membrane  regulation of mitotic spindle organization  lung epithelium development  placenta blood vessel development  regulation of proteasomal protein catabolic process  extracellular exosome  calcium ion transmembrane transport  mesonephric tubule development  mesonephric duct development  metanephric collecting duct development  metanephric ascending thin limb development  metanephric proximal tubule development  metanephric distal tubule morphogenesis  primary cilium  
REACTOMEP98161 [protein]
REACTOME PathwaysR-HSA-5620916 VxPx cargo-targeting to cilium [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkPKD1
Wikipedia pathwaysPKD1
Orthology - Evolution
OrthoDB5310
GeneTree (enSembl)ENSG00000008710
Phylogenetic Trees/Animal Genes : TreeFamPKD1
Homologs : HomoloGenePKD1
Homology/Alignments : Family Browser (UCSC)PKD1
Gene fusions - Rearrangements
Fusion : MitelmanPKD1/SLIT1 [16p13.3/10q24.1]  
Fusion : MitelmanUBE2J2/PKD1 [1p36.33/16p13.3]  [t(1;16)(p36;p13)]  
Polymorphisms : SNP, variants
NCBI Variation ViewerPKD1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PKD1
dbVarPKD1
ClinVarPKD1
1000_GenomesPKD1 
Exome Variant ServerPKD1
ExAC (Exome Aggregation Consortium)PKD1 (select the gene name)
Genetic variants : HAPMAP5310
Genomic Variants (DGV)PKD1 [DGVbeta]
Mutations
ICGC Data PortalPKD1 
TCGA Data PortalPKD1 
Broad Tumor PortalPKD1
OASIS PortalPKD1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPKD1 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Autosomal Dominant Polycystic Kidney Disease (ADPKD)
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch PKD1
DgiDB (Drug Gene Interaction Database)PKD1
DoCM (Curated mutations)PKD1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PKD1 (select a term)
intoGenPKD1
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)16:2138711-2185899  ENSG00000008710
CONAN: Copy Number AnalysisPKD1 
Mutations and Diseases : HGMDPKD1
OMIM173900    601313   
MedgenPKD1
Genetic Testing Registry PKD1
NextProtP98161 [Medical]
TSGene5310
GENETestsPKD1
Huge Navigator PKD1 [HugePedia]
snp3D : Map Gene to Disease5310
BioCentury BCIQPKD1
ClinGenPKD1 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5310
Chemical/Pharm GKB GenePA35521
Clinical trialPKD1
Miscellaneous
canSAR (ICR)PKD1 (select the gene name)
Other databaseADPKD mutation database
Other databaseThe Humane Gene Mutation Database
Probes
Litterature
PubMed226 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePKD1
EVEXPKD1
GoPubMedPKD1
iHOPPKD1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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