Biliary-Atresia-Associated Mannosidase-1-Alpha-2 Gene Regulates Biliary and Ciliary Morphogenesis and Laterality

被引：13

作者：

So, Juhoon ^{[1
]}

Ningappa, Mylarappa ^{[2
]}

Glessner, Joseph ^{[3
]}

Min, Jun ^{[4
,5
]}

Ashokkumar, Chethan ^{[2
]}

Ranganathan, Sarangarajan ^{[6
]}

Higgs, Brandon W. ^{[2
]}

Li, Dong ^{[3
]}

Sun, Qing ^{[2
]}

Schmitt, Lori ^{[7
]}

Biery, Amy C. ^{[6
]}

Dobrowolski, Steven ^{[6
]}

Trautz, Christine ^{[2
]}

Fuhrman, Leah ^{[2
]}

Schwartz, Molly Christine ^{[8
]}

Klena, Nikolai Thomas ^{[8
]}

Fusco, Joseph ^{[9
]}

Prasadan, Krishna ^{[9
]}

Adenuga, Morayooluwa ^{[2
]}

Mohamed, Nada ^{[9
]}

Yan, Qi ^{[10
,11
]}

Chen, Wei ^{[10
,11
]}

Horne, William ^{[12
]}

Dhawan, Anil ^{[13
]}

Sharif, Khalid ^{[14
]}

Kelly, Deirdre ^{[14
]}

Squires, Robert H. ^{[15
]}

Gittes, George K. ^{[9
]}

Hakonarson, Hakon ^{[3
]}

Morell, Victor ^{[16
]}

Lo, Cecilia ^{[8
]}

Subramaniam, Shankar ^{[4
,5
]}

Shin, Donghun ^{[1
]}

Sindhi, Rakesh ^{[2
]}

机构：

[1] Univ Pittsburgh, McGowan Inst Regenerat Med, Dept Dev Biol, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh Med Ctr UPMC, Childrens Hosp Pittsburgh, Hillman Ctr Pediat Transplantat, Pittsburgh, PA USA

[3] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[4] Univ Calif San Diego, Dept Bioengn Cellular & Mol Med, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA

[6] UPMC, Childrens Hosp Pittsburgh, Dept Pathol, Div Pediat Pathol, Pittsburgh, PA USA

[7] UPMC, Childrens Hosp Pittsburgh, Histol Core Lab, Pittsburgh, PA USA

[8] Univ Pittsburgh, Dept Dev Biol, Pittsburgh, PA USA

[9] UPMC, Childrens Hosp Pittsburgh, Pediat Gen & Thorac Surg, Pittsburgh, PA USA

[10] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[11] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA

[12] UPMC, Childrens Hosp Pittsburgh, Richard King Mellon Fdn, Inst Pediat Res, Pittsburgh, PA USA

[13] Kings Coll Hosp London, Paediat Liver GI & Nutr, London, England

[14] Childrens Hosp Birmingham, Birmingham, W Midlands, England

[15] UPMC, Childrens Hosp Pittsburgh, Pediat Gastroenterol, Pittsburgh, PA USA

[16] UPMC, Childrens Hosp Pittsburgh, Dept Cardiothorac Surg, Div Cardiac Surg, Pittsburgh, PA USA

来源：

FRONTIERS IN PHYSIOLOGY | 2020年 / 11卷

关键词：

biliary atresia; liver transplantation; cilia; biliary morphogenesis; laterality; MOLECULAR-GENETICS; ZEBRAFISH; HEART; MICE; EXPRESSION; RECEPTOR;

D O I：

10.3389/fphys.2020.538701

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

Background/Aims 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. Methods 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. Results Single nucleotide polymorphisms in Mannosidase-1-alpha-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. Conclusion 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.

引用

页数：14

共 5 条

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