Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease

Am J Hum Genet. 2003 Mar;72(3):691-703. doi: 10.1086/368295. Epub 2003 Jan 15.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Calcium-Binding Proteins
  • Chromosome Mapping
  • Chromosomes, Human, Pair 19*
  • Cysts / genetics*
  • DNA / blood
  • DNA / genetics
  • Female
  • Genes, Dominant
  • Genetic Linkage
  • Genetic Markers
  • Glucosidases
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Liver Diseases / genetics*
  • Male
  • Membrane Proteins*
  • Molecular Sequence Data
  • Mutation*
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Pedigree
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Point Mutation
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Protein Kinase C / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Alignment
  • Sequence Homology, Amino Acid


  • Calcium-Binding Proteins
  • Genetic Markers
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Myristoylated Alanine-Rich C Kinase Substrate
  • DNA
  • Protein Kinase C
  • Glucosidases
  • PRKCSH protein, human

Associated data

  • GENBANK/AK112399
  • GENBANK/AY058725
  • GENBANK/BC009816
  • GENBANK/D89245
  • GENBANK/J03075
  • GENBANK/U49178
  • OMIM/173900
  • OMIM/173910
  • OMIM/174050