Biliary-Atresia-Associated Mannosidase-1-Alpha-2 Gene Regulates Biliary and Ciliary Morphogenesis and Laterality.
Biliary-Atresia-Associated Mannosidase-1-Alpha-2 Gene Regulates Biliary and Ciliary Morphogenesis and Laterality.
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DOI：
10.3389/fphys.2020.538701
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发表时间：
2020
影响因子：
4
通讯作者：
Sindhi R
中科院分区：
文献类型：
--
作者：
So J;Ningappa M;Glessner J;Min J;Ashokkumar C;Ranganathan S;Higgs BW;Li D;Sun Q;Schmitt L;Biery AC;Dobrowolski S;Trautz C;Fuhrman L;Schwartz MC;Klena NT;Fusco J;Prasadan K;Adenuga M;Mohamed N;Yan Q;Chen W;Horne W;Dhawan A;Sharif K;Kelly D;Squires RH;Gittes GK;Hakonarson H;Morell V;Lo C;Subramaniam S;Shin D;Sindhi R
孤立性胆道闭锁(BA)或综合征性BA(有主要肝外异常)分别涉及感染因素和遗传因素。然而，孤立的BA也与轻微的肝外肠道和心血管异常以及多个易感基因有关，提示共同起源。我们通过全基因组关联、靶向测序和组织染色研究了需要肝移植的BA的新的易感基因，与BA亚型无关。通过斑马鱼基因敲除和小鼠基因敲除模型、小鼠呼吸道细胞培养和肝脏转录组分析，研究了调控左右图案形成的候选基因对形态发生、发育途径和纤毛发生的影响。甘露糖苷酶-1-α-2(mannosidase-1-MAN1A2)单核苷酸多态与BA及其他已知影响MAN1A2表达的多态显著相关，但在两种BA亚型中均未发现差异。在斑马鱼胚胎中，man1a2基因敲除导致胆道网络形成不良，库普弗氏囊纤毛发育不良，心脏和肝脏异位，以及egfra和其他发育基因的失调。次优的man1a2基因敲除与次优的EGFR信号或次优的EGFR途径基因，腺苷核糖化因子-6的次优敲除协同作用，其单独的影响最小，以复制胆管缺陷而不是异质性。在培养的小鼠呼吸道上皮细胞中，Man1a2基因敲除抑制了纤毛的发育和运动。发生呼吸衰竭的Man1a2-/-小鼠也表现出门静脉和胆管炎症。人类BA肝和Man1a2-/-肝表现出Man1a2表达降低和纤毛基因失调，这是已知导致人类多系统偏侧缺陷的原因。需要移植的BA与MAN1A2中的序列变异有关。除肝胆形态发生外，man1a2还通过调节斑马鱼和小鼠的纤毛发生来调节偏侧性，为BA的多系统缺陷提供了新的发育基础。
Infectious and genetic factors are invoked, respectively in isolated biliary atresia (BA), or syndromic BA, with major extrahepatic anomalies. However, isolated BA is also associated with minor extrahepatic gut and cardiovascular anomalies and multiple susceptibility genes, suggesting common origins. We investigated novel susceptibility genes with genome-wide association, targeted sequencing and tissue staining in BA requiring liver transplantation, independent of BA subtype. Candidate gene effects on morphogenesis, developmental pathways, and ciliogenesis, which regulates left-right patterning were investigated with zebrafish knockdown and mouse knockout models, mouse airway cell cultures, and liver transcriptome analysis. Single nucleotide polymorphisms in Mannosidase-1-α-2 (MAN1A2) were significantly associated with BA and with other polymorphisms known to affect MAN1A2 expression but were not differentially enriched in either BA subtype. In zebrafish embryos, man1a2 knockdown caused poor biliary network formation, ciliary dysgenesis in Kupffer’s vesicle, cardiac and liver heterotaxy, and dysregulated egfra and other developmental genes. Suboptimal man1a2 knockdown synergized with suboptimal EGFR signaling or suboptimal knockdown of the EGFR pathway gene, adenosine-ribosylation-factor-6, which had minimal effects individually, to reproduce biliary defects but not heterotaxy. In cultured mouse airway epithelium, Man1a2 knockdown arrested ciliary development and motility. Man1a2–/– mice, which experience respiratory failure, also demonstrated portal and bile ductular inflammation. Human BA liver and Man1a2–/– liver exhibited reduced Man1a2 expression and dysregulated ciliary genes, known to cause multisystem human laterality defects. BA requiring transplantation associates with sequence variants in MAN1A2. man1a2 regulates laterality, in addition to hepatobiliary morphogenesis, by regulating ciliogenesis in zebrafish and mice, providing a novel developmental basis for multisystem defects in BA.
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影响因子：
--
作者：
Molina GA;Watkins SC;Tsang M
通讯作者：
Tsang M
影响因子：
9.8
作者：
Schadt EE;Molony C;Chudin E;Hao K;Yang X;Lum PY;Kasarskis A;Zhang B;Wang S;Suver C;Zhu J;Millstein J;Sieberts S;Lamb J;GuhaThakurta D;Derry J;Storey JD;Avila-Campillo I;Kruger MJ;Johnson JM;Rohl CA;van Nas A;Mehrabian M;Drake TA;Lusis AJ;Smith RC;Guengerich FP;Strom SC;Schuetz E;Rushmore TH;Ulrich R
通讯作者：
Ulrich R
DOI：
10.1038/modpathol.2011.212
发表时间：
2012-05
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Chacko, Balu K.;Scott, David W.;Patel, Rakesh P.
通讯作者：
Patel, Rakesh P.
影响因子：
4.5
作者：
Delous M;Yin C;Shin D;Ninov N;Debrito Carten J;Pan L;Ma TP;Farber SA;Moens CB;Stainier DY
通讯作者：
Stainier DY