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

被引:28
作者
Drenth, JPH
Tahvanainen, E
Morsche, RHMT
Tahvanainen, P
Kääriäinen, H
Höckerstedt, K
van de Kamp, JM
Breuning, MH
Jansen, JBMJ
机构
[1] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA
[2] Univ Med Ctr St Radboud, Dept Med, Div Gastroenterol & Hepatol, Nijmegen, Netherlands
[3] Univ Helsinki, Dept Med Genet, Helsinki, Finland
[4] Natl Publ Hlth Inst, Dept Human Mol Genet, Helsinki, Finland
[5] Univ Turku, Dept Med Genet, Turku, Finland
[6] Turku Univ, Cent Hosp, Dept Pediat, Turku, Finland
[7] Univ Helsinki Hosp, Transplantat & Liver Surg Unit, Helsinki, Finland
[8] Leiden Univ, Med Ctr, Dept Human & Clin Genet, Leiden, Netherlands
关键词
D O I
10.1002/hep.20141
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
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页码:924 / 931
页数:8
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