Disease relevance of PKHD1

• PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells [1].
• PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats [2].
• Forty-seven ARPKD and 14 pedigrees with congenital hepatic fibrosis and/or Caroli's disease, were screened for PKHD1 mutations [3].
• Autosomal recessive polycystic kidney disease (ARPKD) is an inherited cystic disorder that produces renal failure in infants and children and is caused by mutations of PKHD1 [4].
• Genetically based polycystic kidney diseases include autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases, nephronophthisis and medullary cystic disease [5].

Psychiatry related information on PKHD1

• The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD [6].

High impact information on PKHD1

• The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors [7].
• Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality [7].
• A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes [7].
• We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes [8].
• These studies identify a link between two cystic disease genes, HNF1beta (MODY5) and PKHD1 (ARPKD) [4].

Chemical compound and disease context of PKHD1

• In contrast, in polycystic kidneys, those noncystic segments of the nephron from which the cysts are thought to originate (distal nephron (specifically collecting duct)) in ARPKD, primarily distal in ADPKD, proximal and distal in ACKD, had PI values similar to those of the cyst epithelium.(ABSTRACT TRUNCATED AT 400 WORDS)[9]
• These immunohistochemical studies document for the first time ectopic expression of components of the RAS in cystic-dilated tubules of ARPKD and suggest that overactivity of RAS could result in increased intrarenal angiotensin II production, which may contribute to the development of hypertension in ARPKD [10].
• Thus, we assessed cAMP levels and evaluated octreotide (an analogue of somatostatin known to inhibit cAMP) in hepatic cyst growth using an in vitro model of cystogenesis and an in vivo animal model of autosomal recessive polycystic kidney disease (ARPKD), one of the PCLDs [11].
• Treatment of ADPKD cells or ARPKD cells with either Bay K8644, a Ca2+ channel activator, or A23187, a Ca2+ ionophore, caused sustained increases in intracellular Ca2+ levels and completely reversed the mitogenic response to cAMP [12].
• PURPOSE: To describe and analyze the appearances of autosomal recessive polycystic kidney disease (ARPKD) on Tc-99m DMSA and Tc-99m HIDA scintigraphy [13].

Biological context of PKHD1

• HNF-1beta directly regulates the transcription of Pkhd1, and inhibition of PKHD1 gene expression may contribute to the formation of renal cysts in humans with MODY5 [4].
• PKHD1 extends over > or =469 kb, is primarily expressed in human fetal and adult kidney, and includes a minimum of 86 exons that are variably assembled into a number of alternatively spliced transcripts [2].
• The PKHD1-gene products are members of a novel class of proteins that share structural features with hepatocyte growth-factor receptor and plexins and that belong to a superfamily of proteins involved in regulation of cell proliferation and of cellular adhesion and repulsion [2].
• During embryogenesis, PKHD1 is widely expressed in epithelial derivatives, including neural tubules, gut, pulmonary bronchi, and hepatic cells [1].
• Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control [14].

Anatomical context of PKHD1

• 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 [1].
• Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm [15].
• Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a hereditary and severe form of polycystic disease affecting the kidneys and biliary tract with an estimated incidence of 1 in 20,000 live births [16].
• Investigations on the transcript level, however, are hampered as PKHD1 is not widely expressed in blood lymphocytes [17].
• The overall PI of cyst epithelium (excluding hyperplastic cysts) was 2.58 in ADPKD, was 10.5 in ARPKD, and was 3.61 in ACKD [9].

Associations of PKHD1 with chemical compounds

• Pkhd1 expression is inhibited in cystic collecting ducts but not in non-cystic proximal tubules, despite transgene expression in this nephron segment [18].
• To determine whether this increased activity of the EGFR is a functional event that is directly part of the disease pathway of renal cyst formation, we used a genetic approach to introduce a mutant EGFR with decreased tyrosine kinase activity into a murine model of ARPKD [19].
• In short term cultures of human embryonic kidney 293 cells (HEK-293), proteolytic cleavage of fibrocystin can be elicited by stimulation of intracellular Ca(2+) release or activation of protein kinase C. These results identify a novel Ca(2+)-dependent pathway that signals from fibrocystin located in the cell membrane to the nucleus [20].
• Furthermore, Na absorption in ARPKD cells was partially inhibited by 100 micro M apical amiloride or 1 mM basolateral but not apical ouabain [21].
• CONCLUSIONS: In a child with clinically enlarged kidneys that appear diffusely hyperechoic on ultrasound, the appearances on Tc-99m DMSA imaging strongly support the diagnosis of ARPKD [13].

Co-localisations of PKHD1

• In cultured renal cells, the PKHD1 gene product colocalized with polycystin-2, the gene product of autosomal dominant polycystic disease type 2, at the basal bodies of primary cilia [1].

Regulatory relationships of PKHD1

• It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD [22].

Other interactions of PKHD1

• No molecular link between ADPKD and ARPKD has been determined [23].
• Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin [23].
• Simple renal cysts, cystic renal dysplasia, autosomal recessive polycystic kidney disease (ARPKD), and non-cystic, essentially normal kidneys failed to show c-erb B-2 overexpression [24].
• Genomic organization of the KIAA0057 gene that encodes a TRAM-like protein and its exclusion as a polycystic kidney and hepatic disease 1 (PKHD1) candidate gene [25].
• METHODS: cAMP responses to maximally effective concentrations of renal agonists were determined together with measurements of transepithelial anion current and cellular proliferation and extracellular signal-related kinase (ERK 1/2) expression in primary cultures of epithelial cells from human ADPKD and ARPKD cysts [26].

Analytical, diagnostic and therapeutic context of PKHD1

• METHODS: The coding region of PKHD1 was amplified as 79 fragments and analyzed for base pair changes by denaturing high-performance liquid chromatography (DHPLC) [3].
• PKHD1 is highly expressed in adult and infant kidneys and weakly expressed in liver in northern blot analysis [27].
• In situ hybridization analysis further revealed that the expression of PKHD1 in the kidney is mainly localized to the epithelial cells of the collecting duct, the specific tubular segment involved in cyst formation in ARPKD [27].
• Many families who lost a child with severe ARPKD desire an early and reliable prenatal diagnosis (PD) [28].
• METHODS: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1 [29].

References