Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously identified a gene from the mutant locus in a new mouse mutation that causes recessive polycystic kidney disease. Here we describe the cloning, characterization and mapping of the homologous human gene. The human and mouse genes are 95% identical at the predicted amino acid sequence level, and both genes encode a putative protein that contains a tetratricopeptide repeat motif. The human gene, called hTg737, is expressed with a broad tissue distribution that includes the the kidney and liver, and gives rise to a 2.9 kb mRNA. The gene contains 26 exons and spans a genomic region greater than 100 kb. Chromosome mapping experiments revealed that the hTg737 gene maps near the centromere on the long arm of human chromosome 13, at position 13q12.1. While this gene does not map to the primary locus that has been identified for ARPKD in humans, it may represent a candidate gene for other recessive renal disorders that have yet to be mapped.
Hum Mol Genet 1995 Apr
PMID:Characterization of the human homologue of the mouse Tg737 candidate polycystic kidney disease gene. 763 4

Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disorder which usually becomes clinically manifest in early childhood, although the spectrum of ARPKD is much more variable than generally known. Presentation of ARPKD at later ages and survival into adulthood have been observed in many cases. The responsible gene has been mapped to chromosome 6p. Thus there is no evidence of genetic heterogeneity. The most important indication for DNA diagnosis is the prenatal diagnosis in families with at least one affected child. The critical region has been narrowed with the use of recombinant families of about 4 cM. Several possible candidate genes have been excluded.
J Mol Med (Berl) 1998 Apr
PMID:Autosomal recessive polycystic kidney disease. 958 64

Autosomal-recessive polycystic kidney disease (ARPKD) is caused by mutation to a large gene, PKHD1, encoding a putative receptor protein, fibrocystin. We have identified, through analysis of human genomic sequence, a PKHD1 homolog, PKHDL1, in chromosome region 8q23. The PKHDL1 transcript of 13081 bp was amplified as 16 fragments and sequenced; the sequence of the murine ortholog, Pkhdl1 (chromosome region 15B3) was also determined. PKHDL1 contains 78 exons, covers a genomic region of approximately 168 kb and encodes a large protein, fibrocystin-L. Screening PKHDL1 in ARPKD patients with no PKHD1 mutations revealed several sequence variants but no clear mutations, making it unlikely that it is ARPKD-associated. Human fibrocystin-L is predicted to be a large receptor protein (4243 aa; 466 kDa) with a signal peptide, single transmembrane domain and short cytoplasmic tail. Fibrocystin-L is homologous to fibrocystin throughout most of the extracellular region with overall identity of 25.0% and similarity of 41.5%. Fibrocystin-L has extracellular domains similar to fibrocystin with 14 copies of the TIG domain and two regions of significant homology to the protein TMEM2. Genomic sequence analysis identified no other full-length fibrocystin homologs in humans, mice or other sequenced organisms. The Fugu fish has a fibrocystin-L ortholog but no fibrocystin, suggesting that the newly identified protein may be the ancestral form. PKHDL1 and Pkhdl1 are widely expressed at a low level in most tissues but only detected in blood-derived cell-lines. Low level expression was detected in many primary immune cell subtypes but up-regulated specifically in T lymphocytes, following activation signals, suggesting a role in cellular immunity.
Hum Mol Genet 2003 Mar 15
PMID:PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene, encodes a receptor with inducible T lymphocyte expression. 1262 Sep 74

Autosomal recessive polycystic kidney disease (ARPKD) is an infantile form of PKD characterized by fusiform dilation of collecting ducts and congenital hepatic fibrosis. The ARPKD gene, PKHD1, is large (approximately 470 kb; 67 exons) with a 12222 bp longest open reading frame, although multiple different splice forms may be generated. The predicted full-length ARPKD protein, fibrocystin, is membrane bound with 4074 amino acids (447 kDa molecular weight). To characterize the pattern of fibrocystin expression we have generated four monoclonal antibodies (mAb) to the cytoplasmic tail of the protein. Western analysis of human kidney membrane protein showed an identical pattern with each mAb; a strongly expressing large product (>450 kDa), consistent with the predicted protein size, and a weaker approximately 220 kDa band. The same large product was detected in rat and mouse kidney with lower level expression in liver. To further show that these mAbs recognize fibrocystin, tissue from ARPKD patients was analyzed and no fibrocystin products were detected. Immunohistochemical analysis of the developing kidney showed expression in the branching ureteric bud and collecting ducts, expression that persisted into adulthood. Biliary duct staining was found in the liver, plus staining in the pancreas and developing testis. Immunofluorescence analysis of MDCK cells showed a major site of expression in the primary cilia. Recent studies have associated the disease protein in various human and animal forms of PKD with cilia. The localization of fibrocystin to cilia further strengthens that correlation and indicates that the primary defect in ARPKD may be linked to ciliary dysfunction.
Hum Mol Genet 2003 Oct 15
PMID:Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. 1292 74

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of inherited childhood nephropathy ( approximately 1:20,000 live births) characterized by fusiform dilatation of collecting ducts and congenital hepatic fibrosis. Up to 30% die as neonates due to respiratory insufficiency and the majority of surviving infants develop hypertension. Progression to end stage renal disease occurs in 20-45% of cases within 15 years but a proportion maintain renal function into adulthood where complications of liver disease predominate. The ARPKD disease gene, PKHD1, has recently been identified through analysis of an orthologous animal model, the PCK rat. PKHD1 is a large gene ( approximately 470 kb) with 67 exons from which multiple transcripts may be generated by alternative splicing. It is highly expressed in kidney, with lower levels in liver and pancreas. The ARPKD protein, fibrocystin (4074 aa and 447 kDa), is predicted to be an integral membrane, receptor-like protein containing multiple copies of an Ig-like domain (TIG). Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue. In common with other PKD-related proteins, fibrocystin is localized to the primary cilia of renal epithelial cells, reinforcing the link between ciliary dysfunction and cyst development. Screens of PKHD1 have revealed 119 different mutations of various types spread throughout the gene. Several ancestral changes have been described, some localized to specific geographic populations. The majority of patients are compound heterozygotes and preliminary genotype/phenotype studies associate two truncating mutations with severe disease. The complexities of PKHD1, marked allelic heterogeneity and high level of missense changes complicate gene-based diagnostics.
Mol Genet Metab 2004 Feb
PMID:Molecular genetics of autosomal recessive polycystic kidney disease. 1474 Nov 87

Mutations in one copy of the hepatocyte nuclear factors (HNF) 1alpha and 1beta homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.
Hum Mol Genet 2005 Mar 01
PMID:Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. 1564 45

Fibrocystin/polyductin (FPC), the gene product of PKHD1, is responsible for autosomal recessive polycystic kidney disease (ARPKD). This disease is characterized by symmetrically large kidneys with ectasia of collecting ducts. In the kidney, FPC predominantly localizes to the apical domain of tubule cells, where it associates with the basal bodies/primary cilia; however, the functional role of this protein is still unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which FPC was silenced by short hairpin RNA inhibition (shRNA). We showed that inhibition of FPC disrupted tubulomorphogenesis of IMCD cells grown in three-dimensional cultures. Pkhd1-silenced cells developed abnormalities in cell-cell contact, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis, which may be mediated by dysregulation of extracellular-regulated kinase (ERK) and focal adhesion kinase (FAK) signaling. These alterations in cell function in vitro may explain the characteristics of ARPKD phenotypes in vivo.
Mol Biol Cell 2005 Sep
PMID:Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells. 1597 9

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, encoding polycystin-1 (PC1), or PKD2 (polycystin-2, PC2). Autosomal recessive PKD (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). No molecular link between ADPKD and ARPKD has been determined. Here, we demonstrated, by yeast two-hybrid and biochemical assays, that KIF3B, a motor subunit of kinesin-2, associates with PC2 and FPC. Co-immunoprecipitation experiments using Madin-Darby canine kidney (MDCK) and inner medullary collecting duct (IMCD) cells and human kidney revealed that PC2 and KIF3B, FPC and KIF3B and, furthermore, PC2 and FPC are endogenously in the same complex(es), though no direct association between the PC2 and FPC intracellular termini was detected. In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2-KIF3B-FPC complex. This was supported by our observation that altering KIF3B level in IMCD cells by over-expression or siRNA significantly affected complexing between PC2 and FPC. Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells. Furthermore, KIF3B mediated functional modulation of purified PC2 channels by FPC in a planer lipid bilayer electrophysiology system. The FPC C-terminus substantially stimulated PC2 channel activity in the presence of KIF3B, whereas FPC or KIF3B alone had no effect. Taken together, we discovered that kinesin-2 is a linker between PC2 and FPC and mediates the regulation of PC2 channel function by FPC. Our study may be important for elucidating common molecular pathways for PKD of different genotypes.
Hum Mol Genet 2006 Nov 15
PMID:Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. 1700 58

Recent evidence suggests that fibrocystin/polyductin (FPC), polycystin-1 (PC1), and polycystin-2 (PC2) are all localized at the plasma membrane and the primary cilium, where PC1 and PC2 contribute to fluid flow sensation and may function in the same mechanotransduction pathways. To further define the exact subcellular localization of FPC, the protein product encoded by the PKHD1 gene responsible for autosomal recessive polycystic kidney disease (PKD) in humans, and whether FPC has direct and/or indirect cross talk with PC2, which, in turn, is pivotal for the pathogenesis of autosomal dominant PKD, we performed double immunostaining and coimmunoprecipitation as well as a microfluorimetry study of kidney tubular epithelial cells. FPC and PC2 are found to completely or partially colocalize at the plasma membrane and the primary cilium and can be reciprocally coimmunoprecipitated. Although incomplete removal of FPC by small interfering RNA and antibody 803 to intracellular epitopes of FPC did not abolish flow-induced intracellular calcium responses, antibody 804 to extracellular epitopes of FPC blocked cellular calcium responses to flow stimulation. These findings suggest that FPC and polycystins share, at least in part, a common mechanotransduction pathway.
Mol Cell Biol 2007 Apr
PMID:Fibrocystin/polyductin, found in the same protein complex with polycystin-2, regulates calcium responses in kidney epithelia. 1728 55

Mutations at a single locus, PKHD1, are responsible for causing human autosomal recessive polycystic kidney disease (ARPKD). Recent studies suggest that the cystic disease might result from defects in planar cell polarity, but how the 4074 amino acid ciliary protein encoded by the longest open reading frame of this transcriptionally complex gene may regulate this process is unknown. Using novel in vitro expression systems, we show that the PKHD1 gene product polyductin/fibrocystin undergoes a complicated pattern of Notch-like proteolytic processing. Cleavage at a probable proprotein convertase site produces a large extracellular domain that is tethered to the C-terminal stalk by disulfide bridges. This fragment is then shed from the primary cilium by activation of a member of the ADAM metalloproteinase disintegrins family, resulting in concomitant release of an intra-cellular C-terminal fragment via a gamma-secretase-dependent process. The ectodomain of endogenous PD1 is similarly shed from the primary cilium upon activation of sheddases. This is the first known example of this process involving a protein of the primary cilium and suggests a novel mechanism whereby proteins that localize to this structure may function as bi-directional signaling molecules. Regulated release from the primary cilium into the lumen may be a mechanism to distribute signal to down-stream targets using flow.
Hum Mol Genet 2007 Apr 15
PMID:Polyductin undergoes notch-like processing and regulated release from primary cilia. 1747 Apr 60


1 2 3 Next >>