TY - JOUR
T1 - Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease
AU - Li, Airong
AU - Davila, Sonia
AU - Furu, Laszlo
AU - Qian, Qi
AU - Tian, Xin
AU - Kamath, Patrick S.
AU - King, Bernard F.
AU - Torres, Vicente E.
AU - Somlo, Stefan
N1 - Funding Information:
We thank the family members for their generous participation in this study. We thank Kristin Simonson and Patricia Urban for help with patient recruitment, Michael Ott and York Pei for referring patients, Joan Steitz and Richard Lifton for helpful discussions, and Asghar Rastegar for timely support. DNA sequencing was performed by the Keck Biotechnology Resource at Yale. This work was supported by National Institutes of Health (NIH) grant DK51041 (to S.S. and V.E.T.), Mayo Clinic General Clinical Research Center grant M01-RR00585, and Yale Liver Center Training Grant T32 DK07356 (to A.L.). A.L., S.D, L.F, X.T., and S.S. are members of the Yale Center for the Study of Polycystic Kidney Disease (NIH grant P50 DK57328).
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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 ∼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 ∼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.
AB - 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 ∼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 ∼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.
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U2 - 10.1086/368295
DO - 10.1086/368295
M3 - Article
C2 - 12529853
AN - SCOPUS:0037371324
SN - 0002-9297
VL - 72
SP - 691
EP - 703
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -