Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease

Authors

  • Joost P. H. Drenth,

    Corresponding author
    1. Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Center St. Radboud, Nijmegen, The Netherlands
    2. Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
    • Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bldg. 18T, Rm. 101, National Institutes of Health, Bethesda, MD 20892
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    • fax: 301-402-0078

    • Joost P. H. Drenth is an Investigator of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands.

  • Esa Tahvanainen,

    1. Department of Medical Genetics, University of Helsinki, Helsinki, Finland
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  • Rene H. M. te Morsche,

    1. Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Center St. Radboud, Nijmegen, The Netherlands
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  • Pia Tahvanainen,

    1. Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland
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  • Helena Kääriäinen,

    1. Department of Medical Genetics, University of Turku, and Department of Pediatrics, Turku University Central Hospital, Turku, Finland
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  • Krister Höckerstedt,

    1. Transplantation and Liver Surgery Unit, Helsinki University Hospital, Helsinki, Finland
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  • Jiddeke M. van de Kamp,

    1. Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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  • Martijn H. Breuning,

    1. Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
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  • Jan B. M. J. Jansen

    1. Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Center St. Radboud, Nijmegen, The Netherlands
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Abstract

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. (HEPATOLOGY 2004;39:924–931.)

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