title: Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease.
abstract: Autosomal dominant polycystic liver disease (ADPLD) is a distinct clinical and genetic entity that can occur independently from autosomal dominant polycystic kidney disease (ADPKD). We previously studied two large kindreds and reported localization of a gene for ADPLD to an approximately 8-Mb region, flanked by markers D19S586/D19S583 and D19S593/D19S579, on chromosome 19p13.2-13.1. Expansion of these kindreds and identification of an additional family allowed us to define flanking markers CA267 and CA048 in an approximately 3-Mb region containing >70 candidate genes. We used a combination of denaturing high-performance liquid chromatography (DHPLC) heteroduplex analysis and direct sequencing to screen a panel of 15 unrelated affected individuals for mutations in genes from this interval. We found sequence variations in a known gene, PRKCSH, that were not observed in control individuals, that segregated with the disease haplotype, and that were predicted to be chain-terminating mutations. In contrast to PKD1, PKD2, and PKHD1, PRKCSH encodes a previously described human protein termed "protein kinase C substrate 80K-H" or "noncatalytic beta-subunit of glucosidase II." This protein is highly conserved, is expressed in all tissues tested, and contains a leader sequence, an LDLa domain, two EF-hand domains, and a conserved C-terminal HDEL sequence. Its function may be dependent on calcium binding, and its putative actions include the regulation of N-glycosylation of proteins and signal transduction via fibroblast growth-factor receptor. In light of the focal nature of liver cysts in ADPLD, the apparent loss-of-function mutations in PRKCSH, and the two-hit mechanism operational in dominant polycystic kidney disease, ADPLD may also occur by a two-hit mechanism.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Airong
authors.initials: A
authors.lastname: Li
authors.forename: Sonia
authors.initials: S
authors.lastname: Davila
authors.forename: Laszlo
authors.initials: L
authors.lastname: Furu
authors.forename: Qi
authors.initials: Q
authors.lastname: Qian
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Kamath
authors.forename: Bernard F
authors.initials: BF
authors.lastname: King
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D003560:Cysts / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D005959:Glucosidases; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D002135:Calcium-Binding Proteins; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D004247:DNA; D011493:Protein Kinase C; D005959:Glucosidases; C070368:PRKCSH protein, human