Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease.
Mutations in protein kinase C substrate 80K-H (PRKCSH), encoding for the protein hepatocystin, cause autosomal dominant polycystic liver disease (PCLD), which is clinically characterized by the presence of multiple liver cysts. PCLD has been documented in families from Europe (Netherlands, Belgium, Finland) as well as from the United States. In this article, we report results from extensive mutational analysis of the PRKCSH gene in a group of 14 PCLD families and 65 singleton cases of Dutch and Finnish descent with multiple simple liver cysts. We identified PRKCSH mutations in 12 families and in 3 sporadic cases. In 8 of 10 Finnish families we detected the 1437+2delTG splice-site mutation. In Dutch families, we found 2 other mutations that affect correct splicing of PRKCSH: 292+1 G>C (2 families) and 1338-2 A>G (1 family). In another Dutch family, we detected a novel deletion (374-375delAG) in exon 6, predicting an abnormal shortened protein. Investigation of the carrier haplotypes identified a common founder chromosome in unrelated individuals in each of the 3 identified splice-site mutations. In 2 Finnish families with dominantly inherited PCLD, and in 62 of 65 sporadic cases with multiple simple liver cysts, we failed to demonstrate any PRKCSH mutation. This corroborates the notion that autosomal dominant PCLD is genetically heterogeneous. In conclusion, we propose that, on the basis of our results, genetic screening for PRKCSH gene mutations should be limited to patients either with a positive family history for PCLD or who have severe polycystic liver disease.
Drenth
Joost P H
JP
Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Center St. Radboud, Nijmegen, The Netherlands. JoostPHDrenth@CS.com
Tahvanainen
Esa
E
te Morsche
Rene H M
RH
Tahvanainen
Pia
P
Kääriäinen
Helena
H
Höckerstedt
Krister
K
van de Kamp
Jiddeke M
JM
Breuning
Martijn H
MH
Jansen
Jan B M J
JB
D002135:Calcium-Binding Proteins; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D018703:Founder Effect; D005799:Genes, Dominant; D005820:Genetic Testing; D005959:Glucosidases; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008107:Liver Diseases / Q000208:ethnology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D016891:Polycystic Kidney, Autosomal Dominant / Q000208:ethnology / Q000235:genetics*
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D005959:Glucosidases; C070368:PRKCSH protein, human