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http://purl.uniprot.org/citations/27526058http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27526058http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27526058http://www.w3.org/2000/01/rdf-schema#comment"

Objectives

Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy affecting the bile ducts of neonates. Although BA is the leading indication for pediatric liver transplantation, the etiology remains elusive. Adducin 3 (ADD3) and X-prolyl aminopeptidase 1 (XPNPEP1) are 2 genes previously identified in genome-wide association studies as potential BA susceptibility genes. Using zebrafish, we investigated the importance of ADD3 and XPNPEP1 in functional studies.

Methods

To determine whether loss of either gene leads to biliary defects, we performed morpholino antisense oligonucleotide (MO) knockdown studies targeting add3a and xpnpep1 in zebrafish. Individuals were assessed for decreases in biliary function and the presence of biliary defects. Quantitative polymerase chain reaction was performed on pooled 5 days postfertilization larvae to assess variations in transcriptional expression of genes of interest.

Results

Although both xpnpep1 and add3a are expressed in the developing zebrafish liver, only knockdown of add3a produced intrahepatic defects and decreased biliary function. Similar results were observed in homozygous add3a mutants. MO-mediated knockdown of add3a also showed higher mRNA expression of hedgehog (Hh) targets. Inhibition of Hh signaling rescued biliary defects caused by add3a knockdown. Combined knockdown of add3a and glypican-1 (gpc1), another mediator of Hh activity that is also a BA susceptibility gene, resulted in more severe biliary defects than knockdown of either alone.

Conclusions

Our results support previous studies identifying ADD3 as a putative genetic risk factor for BA susceptibility. Our results also provide evidence that add3a may be affecting the Hh pathway, an important factor in BA pathogenesis."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.org/dc/terms/identifier"doi:10.1097/mpg.0000000000001375"xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Cui S."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Cui S."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Matthews R.P."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Matthews R.P."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Tang V."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Tang V."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Loomes K.M."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Loomes K.M."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Cofer Z.C."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Cofer Z.C."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Sapp V."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/author"Sapp V."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/name"J. Pediatr. Gastroenterol. Nutr."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/name"J Pediatr Gastroenterol Nutr"xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/pages"524-530"xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/pages"524-530"xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/title"Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/title"Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish."xsd:string
http://purl.uniprot.org/citations/27526058http://purl.uniprot.org/core/volume"63"xsd:string
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