The significance of human jagged 1 mutations detected in severe cases of extrahepatic biliary atresia

Kohsaka, Takao; Yuan, Zeng rong; Guo, Shuai; Tagawa, Manabu; Nakamura, Akio; Nakano, Masaaki; Kawasasaki, Hideo; Inomata, Yukihiro; Tanaka, Kōichi; Miyauchi, Jun

doi:10.1053/jhep.2002.35820

Cited by 95 publications

(41 citation statements)

References 37 publications

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“…Kohsaka et al found JAG1 mutations in 9 of 102 patients with BA, and these patients appeared to have more severe disease. 32 Because of the association between BA and laterality defects, 5 investigators have examined patients with BA for mutations in genes involved in left/right sidedness. No mutations in INV were identified in 7 patients with BA, 7 whereas CFC1 mutations were found in 5 of 10 patients with BA and laterality defects, 33 although the significance of these mutations is not clear.…”

Section: Discussionmentioning

confidence: 99%

Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene

et al. 2013

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BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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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Section: Discussionmentioning

confidence: 99%

Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene

et al. 2013

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“…Huh-7 cells seeded in a 24-well plate at 2 · 10 4 cells per well in DMEM complete medium and cultured overnight were washed twice with PBS, starved for 5 h in DMEM medium containing 0.5% FBS and treated with 20 ng/mL TNFa (R&D Systems, Minneapolis, MN, USA) to induce IL-8 expression [23]. Cells were grown for an additional 18 h in the presence or absence of 200 lm thalidomide, 10 lm wedelolactone or 13 nm NAI-1.…”

Section: Inhibition Of Il-8 Expression By Thalidomide and Nf-jb Inhibmentioning

confidence: 99%

“…Thalidomide is reported to reduce TNFa-induced IL-8 levels in endometriotic stromal cells [27]. To validate that thalidomide acts similarly in Huh-7 hepatoma cells to inhibit TNFa induction of IL-8 expression [23], exogenous TNFa was added to Huh-7 cell cultures grown in the presence or absence of thalidomide. As thalidomide was reported to inhibit cytokine synthesis by blocking IKK, we also used the IKK-specific inhibitors wedelolactone and NAI-1 that were expected to mimic the action of thalidomide on IKK and thus block IL-8 expression [12].…”

Section: Thalidomide and Ikk Inhibitors Block Il-8 Protein Synthesis mentioning

confidence: 99%

Inhibition of IκB kinase by thalidomide increases hepatitis C virus RNA replication

Rance

Tanner

Alfieri

2011

Journal of Viral Hepatitis

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Hepatic fibrosis is an integral element in the progression of chronic liver disease. Elevated hepatic interleukin (IL)-8 is an important contributor to fibrosis in patients chronically infected with the hepatitis C virus (HCV). Thalidomide has been used to reduce liver inflammation and fibrosis in HCV-infected patients, but its impact on HCV replication remains unclear. This study examined the effect of thalidomide on HCV replication in vitro. Results revealed that while thalidomide reduced IL-8 and nuclear factor kappa B (NF-κB) activity by 95% and 46% in Huh-7 cells, increasing concentrations of thalidomide correlated with a linear rise in HCV replication (17-fold at 200 μm). The NF-κB inhibitors, wedelolactone and NF-κB activation inhibitor-1, which mimic the actions of thalidomide by preventing phosphorylation and activation of IκB kinase (IKK) and hence block NF-κB activity, increased HCV RNA by 18- and 19-fold, respectively. During in vitro HCV replication in Huh-7 cells, we observed a 30% increase in IKKα protein and 55% decrease in NF-κB(p65)/RelA protein relative to cellular β-actin. Ectopic expression of IKKα to enhance the inactive form of IKK in cells undergoing virus replication led to a 13-fold increase in HCV RNA. Conversely, enhanced expression of NF-κB(p65)/RelA in infected cells resulted in a 17-fold reduction in HCV RNA. In conclusion, HCV RNA replication was significantly augmented by the inhibition of IKK activation and subsequent NF-κB signalling, whereas a restoration of NF-κB activity by the addition of NF-κB/RelA markedly reduced HCV replication. This study lends added importance to the role of the NF-κB signalling pathway in controlling HCV replication.

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“…We previously showed that common variants with footprints of genetic-environmental interaction confer risk of BA. Also, a handful of rare mutations has been detected in syndromic BA or non-syndromic BA with severe clinical manifestations [3–7]. Overall, BA represents a rare disease with a complex genetic architecture.…”

Section: Introductionmentioning

confidence: 99%

“…Although exploration on the developmental candidate gene mutation in BA was fruitful, its value is limited as individual finding that may represent only a heterogeneous group of patients [5–7]. …”

Section: Introductionmentioning

confidence: 99%

Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis

et al. 2017

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BackgroundBiliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance.MethodsThe study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case–control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network.ResultsOf the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers’ immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway.ConclusionsThe study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0259-0) contains supplementary material, which is available to authorized users.

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The significance of human jagged 1 mutations detected in severe cases of extrahepatic biliary atresia

Cited by 95 publications

References 37 publications

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

Inhibition of IκB kinase by thalidomide increases hepatitis C virus RNA replication

Patient complexity and genotype-phenotype correlations in biliary atresia: a cross-sectional analysis

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