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

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease that presents primarily in infancy and childhood and that is characterized by enlarged kidneys and congenital hepatic fibrosis. We have identified PKHD1, the gene mutated in ARPKD. 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. The longest continuous open reading frame encodes a 4,074-amino-acid protein, polyductin, that is predicted to have a single transmembrane (TM)-spanning domain near its carboxyl terminus, immunoglobulin-like plexin-transcription-factor domains, and parallel beta-helix 1 repeats in its amino terminus. Several transcripts encode truncated products that lack the TM and that may be secreted if translated. 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.

Fibrocystin/Polyductin Modulates Renal Tubular Formation by Regulating Polycystin-2 Expression and Function

“…Although the gene responsible for ARPKD, PKHD1, has been identified [23][24][25] and its gene product, FPC, has been initially characterized, 27,28,30,31,39,40 the mechanisms by which PKHD1 causes disease phenotypes remain largely unknown. To study the disease mechanism and pathogenesis of ARPKD, we created a mouse that allows manipulation of Pkhd1, an animal model that recapitulates the human ARPKD phenotype.…”

“…The longest open reading frame is predicted to include 66 exons and to encode the 4074 -amino acid membrane-associated receptor-like protein fibrocystin/polyductin (FPC). [23][24][25][26] It was shown that FPC is associated with the basal bodies/primary cilia of epithelial cells [27][28][29][30] and co-localizes with PC2 within the cell. 31 These observations suggest the possibility that FPC and PC2 may function in a common molecular pathway in vivo.…”

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

“…[2][3][4] Mutations to orthologous genes, PKHD1/Pkhd1, have been identified in ARPKD patients and the PCK rat. 6,7 Developing and mature intrahepatic bile ducts express the PKHD1 protein, fibrocystin, whereas bile ducts of ARPKD patients lack its expression. 8 Mice with targeted mutation of Pkhd1 develop cystic biliary dysgenesis and portal fibrosis.…”

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference

“…3,4 Mutations are distributed throughout the gene, and polymorphisms are common.5 , 10 The current mutation detection rate is 80% to 85%. 5 ,10 There is marked allelic heterogeneity, and most affected patients appear to be compound heterozygotes.…”

“…[1][2][3][4][5] Fibrocystin/polyductin, the protein encoded by PKHD1, is expressed on the primary cilia of renal and bile duct epithelial cells and is believed to function to maintain the 3-dimensional tubular architecture. 6 Kidney cysts in ARPKD are nonobstructive dilations of the collecting ducts.…”