The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

Abstract

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. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. 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. 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. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

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.…”