title: Isolated polycystic liver disease genes define effectors of polycystin-1 function.
abstract: Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.
authors.forename: Whitney
authors.initials: W
authors.lastname: Besse
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
authors.forename: Jungmin
authors.initials: J
authors.lastname: Choi
authors.forename: Sohan
authors.initials: S
authors.lastname: Punia
authors.forename: Sorin V
authors.initials: SV
authors.lastname: Fedeles
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Anna-Rachel
authors.initials: AR
authors.lastname: Gallagher
authors.forename: Emily B
authors.initials: EB
authors.lastname: Huang
authors.forename: Ashima
authors.initials: A
authors.lastname: Gulati
authors.forename: James
authors.initials: J
authors.lastname: Knight
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.forename: Esa
authors.initials: E
authors.lastname: Tahvanainen
authors.forename: Pia
authors.initials: P
authors.lastname: Tahvanainen
authors.forename: Simone
authors.initials: S
authors.lastname: Sanna-Cherchi
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Terry
authors.initials: T
authors.lastname: Watnick
authors.forename: York P
authors.initials: YP
authors.lastname: Pei
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
mesh_terms: D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins; D002461:Cell Line, Transformed; D003560:Cysts / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D005959:Glucosidases / Q000235:genetics / Q000378:metabolism; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones; D009154:Mutation; D016601:RNA-Binding Proteins; D000069816:SEC Translocation Channels / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000096:biosynthesis / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D005959:Glucosidases; D005964:Glucosyltransferases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D016601:RNA-Binding Proteins; D000069816:SEC Translocation Channels; D050396:TRPP Cation Channels; C499388:SEC61B protein, human; C487464:SEC63 protein, human; C473777:ALG8 protein, human; C070368:PRKCSH protein, human