Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene.
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DOI：
10.1053/j.gastro.2013.01.022
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发表时间：
2013-05
期刊：
影响因子：
29.4
通讯作者：
Matthews RP
中科院分区：
文献类型：
--
作者：
Cui S;Leyva-Vega M;Tsai EA;EauClaire SF;Glessner JT;Hakonarson H;Devoto M;Haber BA;Spinner NB;Matthews RP
胆道闭锁（BA）是一种婴儿进行性纤维炎症性疾病，涉及肝外和肝内胆管树。其病因尚不清楚，但据信涉及遗传易感个体暴露于某些环境因素。BA仅发生在新生儿肝脏，因此肝胆发育过程中表达的基因变异可能影响易感性。全基因组关联研究先前在2q37确定了一个潜在的感兴趣区域。我们继续这些研究以缩小该区域并确定BA易感基因。
我们寻找在BA患者（n = 61）中相较于健康个体（对照组；n = 5088）增加的拷贝数变异。在确定一个候选基因后，我们研究了斑马鱼肝脏中同源基因的表达模式，以及用吗啉反义寡核苷酸降低表达对胆管发育、基因表达和信号转导的影响。
我们观察到BA患者在2q37.3处的缺失有统计学上的显著增加，这导致了GPC1的一个拷贝缺失，GPC1编码磷脂酰肌醇蛋白聚糖1，一种调节刺猬信号和炎症的硫酸乙酰肝素蛋白聚糖。在斑马鱼中敲低gpc1导致胆管发育缺陷。将gpc1吗啉代寡核苷酸处理的斑马鱼暴露于环巴胺（一种刺猬信号拮抗剂）可部分挽救gpc1敲低的表型。给斑马鱼注射重组音猬因子导致与gpc1吗啉代寡核苷酸处理的斑马鱼相似的胆管缺陷。与对照组样本相比，BA患者的肝脏样本中胆管细胞顶端的GPC1水平降低。
基于对BA患者和斑马鱼的基因分析，GPC1似乎是一个BA易感基因。这些发现也支持刺猬信号在BA发病机制中的作用。
Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls. Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA.
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影响因子：
30.8
作者：
Cullinane AR;Straatman-Iwanowska A;Zaucker A;Wakabayashi Y;Bruce CK;Luo G;Rahman F;Gürakan F;Utine E;Ozkan TB;Denecke J;Vukovic J;Di Rocco M;Mandel H;Cangul H;Matthews RP;Thomas SG;Rappoport JZ;Arias IM;Wolburg H;Knisely AS;Kelly DA;Müller F;Maher ER;Gissen P
通讯作者：
Gissen P
影响因子：
5.1
作者：
Davenport, Mark;Tizzard, Sarah A.;Hadzic, Nedim
通讯作者：
Hadzic, Nedim
影响因子：
30.8
作者：
Gissen, P;Johnson, CA;Maher, ER
通讯作者：
Maher, ER
DOI：
10.1097/01.mpg.0000192247.55583.fa
发表时间：
2006-01-01
影响因子：
2.9
作者：
Arikan, C;Berdeli, A;Aydogdu, S
通讯作者：
Aydogdu, S
影响因子：
25.7
作者：
Folseraas, Trine;Melum, Espen;Rausch, Philipp;Juran, Brian D.;Ellinghaus, Eva;Shiryaev, Alexey;Laerdahl, Jon K.;Ellinghaus, David;Schramm, Christoph;Weismueller, Tobias J.;Gotthard, Daniel Nils;Hov, Johannes Roksund;Clausen, Ole Petter;Weersma, Rinse K.;Janse, Marcel;Boberg, Kirsten Muri;Bjornsson, Einar;Marschall, Hanns-Ulrich;Cleynen, Isabelle;Rosenstiel, Philip;Holm, Kristian;Teufel, Andreas;Rust, Christian;Gieger, Christian;Wichmann, H-Erich;Bergquist, Annika;Ryu, Euijung;Ponsioen, Cyriel Y.;Runz, Heiko;Sterneck, Martina;Vermeire, Severine;Beuers, Ulrich;Wijmenga, Cisca;Schrumpf, Erik;Manns, Michael P.;Lazaridis, Konstantinos N.;Schreiber, Stefan;Baines, John F.;Franke, Andre;Karlsen, Tom H.
通讯作者：
Karlsen, Tom H.