Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis
Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis
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DOI：
10.1073/pnas.1309438111
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发表时间：
2014-04-08
影响因子：
11.1
通讯作者：
Drenth, Joost P. H.
中科院分区：
文献类型：
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作者：
Cnossen, Wybrich R.;te Morsche, Rene H. M.;Drenth, Joost P. H.
多囊肝见于罕见的遗传性疾病孤立性多囊肝病（PCLD），并被认为是常染色体显性遗传性多囊肾病最常见的肾外表现。肝囊肿形成的特征是胆管细胞的进行性增殖，最终导致肝肿大。从遗传学角度来看，多囊性肝病是一种不完全外显的异质性疾病，由PRKCSH、SEC 63、PKD 1或PKD 2突变引起。全基因组SNP分型和桑格测序显示，在一个扩展的PCLD家族中，迄今为止没有致病性基因变异。我们对两名成员的DNA样品进行了全外显子组测序。位于低密度脂蛋白受体相关蛋白5（LRP 5）基因中高度保守氨基酸位置（p.R1188W）的杂合变异c.3562C > T与疾病分离（比值分数的对数，4.62），但在1,000多名未受影响的个体中未观察到。在PCLD队列中筛选LRP 5发现了三个多囊肝无关家族中的三个额外突变（p.V454M，p.R1529S和p.D1551N），同样在对照组中未检测到。预测所有变体对LRP 5蛋白结构域具有深刻的结构影响。肝囊肿组织和正常肝组织标本患者和对照组显示丰富的LRP 5表达的免疫组化。功能活性分析表明，突变体LRP 5导致减少无翅信号激活。总之，我们证明了生殖系LRP 5错义突变与肝囊肿发生相关。这项研究的发现将PCLD的病理生理学与经典无翅信号通路的失调联系起来。
Polycystic livers are seen in the rare inherited disorder isolated polycystic liver disease (PCLD) and are recognized as the most common extrarenal manifestation in autosomal dominant polycystic kidney disease. Hepatic cystogenesis is characterized by progressive proliferation of cholangiocytes, ultimately causing hepatomegaly. Genetically, polycystic liver disease is a heterogeneous disorder with incomplete penetrance and caused by mutations in PRKCSH, SEC63, PKD1, or PKD2. Genome-wide SNP typing and Sanger sequencing revealed no pathogenic variants in hitherto genes in an extended PCLD family. We performed whole-exome sequencing of DNA samples from two members. A heterozygous variant c.3562C > T located at a highly conserved amino acid position (p.R1188W) in the low density lipoprotein receptor-related protein 5 (LRP5) gene segregated with the disease (logarithm of odds score, 4.62) but was not observed in more than 1,000 unaffected individuals. Screening of LRP5 in a PCLD cohort identified three additional mutations in three unrelated families with polycystic livers (p.V454M, p.R1529S, and p.D1551N), again all undetected in controls. All variants were predicted to be damaging with profound structural effects on LRP5 protein domains. Liver cyst tissue and normal hepatic tissue samples from patients and controls showed abundant LRP5 expression by immunohistochemistry. Functional activity analyses indicated that mutant LRP5 led to reduced wingless signal activation. In conclusion, we demonstrate that germ-line LRP5 missense mutations are associated with hepatic cystogenesis. The findings presented in this study link the pathophysiology of PCLD to deregulation of the canonical wingless signaling pathway.