Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease
Abnormal hepatocystin caused by truncating PRKCSH mutations leads to autosomal dominant polycystic liver disease
复制标题
DOI：
10.1002/hep.20141
复制
发表时间：
2004-04-01
期刊：
影响因子：
13.5
通讯作者：
Jansen, JBMJ
中科院分区：
文献类型：
--
作者：
Drenth, JPH;Tahvanainen, E;Jansen, JBMJ
蛋白激酶C底物80 K-H（PRKCSH）编码蛋白质肝囊肿素，其突变引起常染色体显性遗传性多囊肝病（PCLD），其临床特征是存在多个肝囊肿。在欧洲（荷兰、比利时、芬兰）以及美国的家庭中，都有PCLD的记录。在这篇文章中，我们报告了一组14个PCLD家族和65例荷兰和芬兰血统的多个单纯性肝囊肿的PRKCSH基因的广泛突变分析结果。我们在12个家族和3个散发病例中发现了PRKCSH突变。在10个芬兰家庭中的8个，我们检测到1437+2delTG剪接位点突变。在荷兰家族中，我们发现了另外2个影响PRKCSH正确剪接的突变：292+1 G>C（2个家族）和1338-2 A>G（1个家族）。在另一个荷兰家族中，我们检测到外显子6的一个新缺失（374- 375 delAG），预测异常缩短蛋白。对携带者单倍型的调查在3个确定的剪接位点突变中的每一个中确定了一个不相关个体的共同创始者染色体。在2个显性遗传PCLD的芬兰家族中，以及在65例多发性单纯性肝囊肿的散发病例中的62例中，我们未能证明任何PRKCSH突变。这证实了常染色体显性PCLD是遗传异质性的概念。总之，我们建议，在我们的研究结果的基础上，PRKCSH基因突变的遗传筛查应仅限于具有PCLD阳性家族史或患有严重多囊肝病的患者。
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.