Alternative titles; symbols
HGNC Approved Gene Symbol: PKHD1
Cytogenetic location: 6p12.3-p12.2 Genomic coordinates (GRCh38): 6:51,615,299-52,087,615 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p12.3-p12.2 | Polycystic kidney disease 4, with or without hepatic disease | 263200 | Autosomal recessive | 3 |
Ward et al. (2002) identified a gene encoding a large, receptor-like protein as the site of mutations causing autosomal recessive polycystic kidney disease (PKD4; 263200), also known as polycystic kidney and hepatic disease-1, and designated the protein fibrocystin. Identification of the gene came from study of a rat model in which the gene for autosomal recessive polycystic kidney disease mapped to rat chromosome 9 in a region of syntenic homology to a portion of the human chromosome 6 containing the locus for ARPKD. The PKHD1 open reading frame is 12,222 basepairs and encodes a protein of 4,074 amino acids. Ward et al. (2002) found that the PKHD1 transcript, approximately 16 kb long, is expressed at moderate levels in adult kidney and pancreas, with lower expression in liver. Moderate expression was also detected in fetal kidney. The large protein encoded by PKHD1 contains multiple copies of a domain, TIG, shared with plexins and transcription factors. It was thought that fibrocystin may be a receptor protein that acts in collecting duct and biliary differentiation.
Onuchic et al. (2002) identified several distinct PKHD1 transcripts containing unique combinations of exons. The transcript with the longest open reading frame encoded a deduced 4,074-amino acid integral membrane protein, which the authors designated polyductin. This protein has a 3,858-amino acid extracellular N terminus, a single transmembrane (TM) domain, and a short C terminus. The extracellular region contains 6 immunoglobulin-like plexin (see 601055)-transcription factor (IPT) domains, followed by at least 9 HbH1 repeats, which are commonly associated with polysaccharidases. It also has multiple potential N-glycosylation sites, an RGD domain, and 3 putative cAMP/cGMP phosphorylation sites. The other PKHD1 gene products were predicted to fall into 2 broad groups: those that encode proteins containing the TM element, which are likely to be associated with the plasma membrane, and those that encode proteins lacking the TM domain, which are likely to be secreted. Northern blot analysis detected a smear of transcripts from 8.5 to 13 kb, with highest expression in adult and fetal kidney. Adult kidney showed strong diffuse bands of about 9.0 and 12.0 kb, and fetal kidney showed smaller and more uniformly sizes transcripts. PKHD1 expression was also detected at much lower levels in pancreas and liver, but not in any other tissue examined.
Ward et al. (2002) detected 67 exons of the PKHD1 gene spanning 472 kb of genomic DNA. The open reading frame begins in exon 2.
Onuchic et al. (2002) determined that the PKHD1 gene contains at least 86 exons and may span as much as 643 kb.
Zerres et al. (1994) mapped the gene for autosomal recessive polycystic kidney disease to chromosome 6p21-cen by linkage analysis, and Mucher et al. (1994) refined the assignment to chromosome 6p21.1-p12. Guay-Woodford et al. (1995) refined the location of the PKHD1 gene to a 3.8-cM interval on chromosome 6p21.1-p12.
Gross (2016) mapped the PKHD1 gene to chromosome 6p12.3-p12.2 based on an alignment of the PKHD1 sequence (GenBank AF480064) with the genomic sequence (GRCh38).
The human PKHD1 gene maps to chromosome 6 in a region sharing syntenic homology with a region of rat chromosome 9 that contains the gene mutant in autosomal recessive polycystic kidney disease (ARPKD) (Ward et al., 2002).
Zhang et al. (2004) found that Pkhd1 was widely expressed in epithelial derivatives, including neural tubules, gut, pulmonary bronchi, and hepatic cells, during mouse embryogenesis. In the kidneys of pck rats, a genetic model of ARPKD, Pkhd1 expression was significantly reduced, but not completely absent. In cultured renal cells of diverse mammalian origin, Pkhd1 colocalized with polycystin-2 at the basal bodies of primary cilia. Immunoreactive Pkhd1 localized predominantly at the apical domain of polarized epithelial cells, suggesting it may be involved in the tubulogenesis and/or maintenance of duct-lumen architecture.
Kaimori et al. (2007) found that the PKHD1 protein underwent a complicated pattern of proteolytic processing, similar to that found for NOTCH (see 190198). Cleavage at a probable proprotein convertase site produced a large extracellular domain that was tethered to the remaining membrane-bound C-terminal stalk via disulfide bridges. This fragment was shed from the primary cilium by activation of a member of the ADAM family of proteases (see 601533), and this shedding permitted the concomitant regulated release of an intracellular C-terminal fragment via a gamma-secretase (see 104311)-dependent process. Endogenous PKHD1 that localized to the primary cilium underwent regulated shedding and intramembrane proteolysis following calcium mobilization. This intracellular C-terminal fragment translocated to the nucleus in a manner similar to the NOTCH intracellular domain.
Zhang et al. (2010) reported that endogenous PKHD1 localized to the centrosome and mitotic spindle of dividing cells in multiple cell lines. Using short hairpin-mediated RNA interference, the authors showed that the inhibition of PKHD1 function in MDCK and mIMCD3 cells led to centrosome amplification, chromosome lagging, and multipolar spindle formation. Consistent with in vitro findings, centrosome amplification in kidneys from human ARPKD patients was also observed. The authors concluded that PKHD1 has a novel function in centrosome duplication and mitotic spindle assembly during cell division, and that mitotic defects due to PKHD1 dysfunction contribute to cystogenesis in ARPKD.
Using Western blot analysis and immunohistochemical methods, Ward et al. (2003) demonstrated a lack of antibody staining for fibrocystin in tissue from ARPKD patients. Normal developing kidney showed expression in the branching ureteric bud and collecting ducts that persisted into adulthood. Staining was also found in hepatic biliary ducts, pancreas, and developing testis. Immunofluorescence analysis of kidney epithelial (MDCK) cells showed a major site of expression in the primary cilia, suggesting to the authors that the primary defect in ARPKD may be linked to ciliary dysfunction.
Polycystic Kidney Disease 4
Ward et al. (2002) screened the entire coding region of the PKHD1 gene for mutations in 14 probands clinically diagnosed or suspected of having autosomal recessive polycystic kidney disease (ARPKD). Denaturing high-performance liquid chromatography (DHPLC) detected 6 truncating and 12 missense mutations in patients with PKD4 (263200). Eight of the affected individuals were compound heterozygotes. No individual was homozygous for a truncating mutation. In 1 pedigree with compound heterozygosity for a missense and a truncating mutation (see 606702.0005), the disease presented in adulthood and was not associated with severe kidney disease in 2 of 3 affected sibs.
Bergmann et al. (2003) stated that 29 different PKHD1 mutations had been described. They reported mutation screening in 90 ARPKD patients and identified mutations in 110 alleles, a detection rate of 61%. Thirty-four of the detected mutations had not previously been reported. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Approximately 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin ortholog. One recurrent mutation, T36M (606702.0001), was thought to represent a mutation hotspot and was found in a variety of populations. Two founder mutations, R496X (606702.0007) and V3471G (606702.0008), comprised approximately 60% of PKHD1 mutations in the Finnish population.
Bergmann et al. (2004) provided an update compiling all known PKHD1 mutations and polymorphisms/sequence variants. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Most were unique to single families ('private mutations'). All patients carrying 2 truncating mutations displayed a severe phenotype with perinatal or neonatal demise, whereas patients surviving the neonatal period carried at least 1 missense mutation. Some missense changes, however, were as devastating as truncating mutations.
In a series of 40 apparently unrelated families with ARPKD with at least 1 perinatally or neonatally deceased child, Bergmann et al. (2004) performed PKHD1 mutation screening by DHPLC. They observed 68 out of an expected 80 mutations, corresponding to a detection rate of 85%. Among the mutations identified, 23 were not previously reported. Bergmann et al. (2004) detected 2 underlying mutations in 29 families and 1 in 10 families. Thus, in all but 1 family (98%), they were able to identify at least 1 mutation substantiating the diagnosis of PKD4. Approximately two-thirds of the changes were predicted to truncate the protein.
Bergmann et al. (2005) stated that a total of 263 different PKHD1 mutations (found in 639 mutated alleles) had been registered in the their locus-specific database. DHPLC-based mutational studies reported detection rates of about 80% and a minimum of 1 PKHD1 mutation found in more than 95% of families. Except for a few population-specific founder alleles and the common T36M mutation (606702.0001), PKHD1 is characterized by allelic diversity. Bergmann et al. (2005) pointed out that about 80% of known PKHD1 mutations could be identified if a subset of 27 out of 77 DHPLC fragments is screened.
Adeva et al. (2006) commented that the autosomal recessive form of polycystic kidney disease was generally considered an infantile disorder with the typical presentation of greatly enlarged echogenic kidneys detected in utero or within the neonatal period, often resulting in neonatal demise. They retrospectively reviewed the clinical records, and where possible performed PKHD1 mutation screening, in patients diagnosed with ARPKD or congenital hepatic fibrosis at the Mayo Clinic from 1961 to 2004. They found 65 cases that were considered to meet the diagnostic criteria with an average duration of follow-up of 8.6 +/- 6.4 years. ARPKD was present in 55 cases and 10 had isolated congenital hepatic fibrosis with no or minimal renal involvement. Mutation analysis was performed in 31 families and at least 1 mutation was detected in 25 (81%), with 76% of mutant alleles detected in those cases. Consistent with the relatively mild disease manifestations in this particular group of patients, most of the changes were missense (79%) and no case had 2 truncating changes. Mutations were detected in all diagnostic groups, indicating that congenital hepatic fibrosis with minimal kidney involvement can result from PKHD1 mutation.
Losekoot et al. (2005) performed mutation analysis of the PKHD1 gene by direct sequencing of the 67 exons of the longest transcript, that encoding the protein fibrocystin/polyductin. They studied 39 mainly Dutch families segregating PKD and identified 68 mutations on the 78 chromosomes. Some of these mutations were derived from common ancestors; others could be recurrent. There was clearly no indication of mutation hotspots.
Role in Cancer
Using high-throughput screening of 14,662 human protein coding transcripts, Sjoblom et al. (2006) found that the PKHD1 gene was the seventh most common somatically mutated gene in colorectal cancer (114500).
Ward et al. (2011) observed an association between the common T36M (606702.0001) allele and protection against colorectal cancer. Germline heterozygosity for the mutant allele was found in 0.42% of 3,603 healthy European controls and in 0.027% of 3,767 patients with colorectal cancer (p = 0.0002; odds ratio of 0.072). Combined with data from a group of patients with ARPKD, Ward et al. (2011) estimated the frequency of T36M to be 3.2% in the European population.
Lager et al. (2001) and Sanzen et al. (2001) described a rat model of autosomal recessive polycystic kidney disease in which the animals developed collecting duct-derived renal cysts, ductal plate malformations, and hepatic cystic disease, similar to human ARPKD. Ward et al. (2002) mapped the Pkhd1 gene, defective in the 'polycystic kidney' (Pck) rat, to chromosome 9 and found a frameshift mutation as the cause of the phenotype.
Hiesberger et al. (2004) identified an evolutionarily conserved transcription factor-2 (TCF2, or HNF1B; 189907)-binding site in the proximal promoter of the mouse Pkhd1 gene. Wildtype Tcf2 and the structurally related Tcf1 (142410) were noted to bind specifically to the Pkhd1 promoter and activate gene transcription. Expression of a dominant-negative Tcf2 mutant inhibited Pkhd1 expression and produced renal cysts in transgenic mice. Pkhd1 transcripts were absent in the cells lining the cysts but were present in morphologically normal surrounding tubules. The authors concluded that TCF2 directly regulates the transcription of PKHD1 and that inhibition of PKHD1 gene expression may contribute to the formation of renal cysts in humans with maturity-onset diabetes of the young type V (MODY5; 137920).
Using a combination of targeted knockout and overexpression with 2 genes mutated in polycystic liver disease (PCLD; 174050), Prkcsh (177060) and Sec63 (608648), and 3 genes mutated in polycystic kidney disease, Pkd1 (601313), Pkd2 (173910), and Pkhd1, Fedeles et al. (2011) produced a spectrum of cystic disease severity in mice. Cyst formation in all combinations of these genes, except complete loss of Pkd2, was significantly modulated by altering expression of Pkd1. Proteasome inhibition increased the steady-state levels of Pkd1 in cells lacking Prkcsh and reduced cystic disease in mouse models of autosomal dominant polycystic liver disease. Fedeles et al. (2011) concluded that PRKCSH, SEC63, PKD1, PKD2, and PKHD1 form an interaction network with PKD1 as the rate-limiting component.
In a female infant in whom the diagnosis of autosomal recessive polycystic kidney disease (PKD4; 263200) was made in utero, Ward et al. (2002) found a 107C-T transition in exon 3 of the PKHD1 gene resulting in a thr36-to-met (T36M) amino acid substitution in fibrocystin. The infant, who had congenital hepatic fibrosis, required mechanical ventilation at birth and was hypertensive. The patient suffered hematemesis at 3 years of age and had variceal banding.
Bergmann et al. (2003) concluded that the T36M mutation represents a mutation hotspot because it is recurrent and observed in a variety of populations.
Ward et al. (2011) estimated the frequency of T36M to be 3.2% in the European population. Ward et al. (2011) observed an association between the common T36M allele and protection against colorectal cancer (114500). Germline heterozygosity for the mutant allele was found in 0.42% of 3,603 healthy European controls and in 0.027% of 3,767 patients with colorectal cancer (p = 0.0002; odds ratio of 0.072). The authors postulated that reduced fibrocystin activity may enhance mitotic instability, which may inhibit carcinogenesis.
In a female infant in whom the diagnosis of autosomal recessive polycystic kidney disease (PKD4; 263200) was made at the age of 9 months on the basis of abdominal mass, Ward et al. (2002) found compound heterozygosity for 2 missense mutations in the PKHD1 gene: ser1664 to phe (S1664F), resulting from a 4991C-T transition, and ser3018 to phe (S3018F; 606702.0003), resulting from a 9053C-T transition. The infant had congenital hepatic fibrosis and Caroli disease. Bilateral inguinal hernias, pyloric stenosis, and very low uric acid were also described.
For discussion of the ser3018-to-phe (S3018F) mutation in the PKHD1 gene that was found in compound heterozygous state in a patient with autosomal recessive polycystic kidney disease (PKD4; 263200) by Ward et al. (2002), see 606702.0002.
In a man in whom the diagnosis of autosomal recessive polycystic kidney disease (PKD4; 263200) was first made at the age of 25 years on the basis of flank pain, Ward et al. (2002) found a val1741-to-met (V1741M) missense mutation in exon 32 of the PKHD1 gene, resulting from a 5221G-A nucleotide change. He had polycystic kidneys by renal imaging, but predominant changes were in the liver, which showed both congenital hepatic fibrosis and Caroli disease. He had esophageal varices, cholangitis, and splenomegaly. The patient did not have hypertension, and serum creatinine at the age of 41 years was 1.8.
Ward et al. (2002) described compound heterozygosity for 2 mutations in the PKHD1 gene in a brother and 2 sisters with autosomal recessive polycystic kidney disease (PKD4; 263200) diagnosed at ages 37, 42, and 42 years, respectively: arg2671 to ter (R2671X), inherited from the mother, and ile3553 to thr (I3553T; 606702.0006), inherited from the father. The truncating mutation resulted from an 8011C-T transition in exon 50; the missense mutation, from a 10658T-C transition in exon 61. One of the sisters had a single renal cyst; the other sister had multiple renal cysts. The brother had Caroli disease but not congenital hepatic fibrosis; the sisters had congenital hepatic fibrosis but not Caroli disease.
For discussion of the ile3553-to-thr (I3553T) mutation in the PKHD1 gene that was found in compound heterozygous state in sibs with polycystic kidney disease (PKD4; 263200) by Ward et al. (2002), see 606702.0005.
In patients from 18 Finnish families with autosomal recessive polycystic kidney disease (PKD4; 263200), Bergmann et al. (2003) identified a 1486C-T transition in exon 16 of the PKHD1 cDNA sequence, resulting in an arg496-to-ter (R496X) mutation. In patients from 5 other Finnish families with the disease, they identified a 10412T-G transversion in exon 61 of the cDNA sequence, resulting in a val3471-to-gly (V3471G; 606702.0008) mutation. Bergmann et al. (2003) noted that these 2 founder mutations comprised approximately 60% of PKHD1 mutations in the Finnish population.
For discussion of the val3471-to-gly (V3471G) mutation in the PKHD1 gene that was found in compound heterozygous state in patients with autosomal recessive polycystic kidney disease (PKD4; 263200) by Bergmann et al. (2003), see 606702.0007.
In affected members of 4 unrelated French families with autosomal recessive polycystic kidney disease (PKD4; 263200), Michel-Calemard et al. (2009) identified an A-to-G transition deep within intron 46 of the PKHD1 gene, resulting in a novel donor splice site, an out-of-frame insertion of a pseudoexon, and premature termination in exon 47. Each patient was compound heterozygous for the IVS46 mutation and another pathogenic mutation in the PKHD1 gene. Haplotype analysis indicated a founder effect for the IVS46 mutation. The mutation was not identified in 100 control alleles.
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