Exome Sequencing in Individuals with Isolated Biliary Atresia

Rajagopalan, Ramakrishnan; Tsai, Ellen; Grochowski, Christopher M.; Kelly, Susan; Loomes, Kathleen M.; Spinner, Nancy B.; Devoto, Marcella

doi:10.1038/s41598-020-59379-4

Cited by 19 publications

(17 citation statements)

References 52 publications

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“…These studies showed that EHC and IHC depend on distinct arms of the glutathione metabolism pathway to maintain redox homeostasis. Our work further revealed that protein quality control (PQC) mechanisms work in concert with redox responses following biliatresone exposure, and genetic disruption of the heat shock chaperone 90 (HSP90) pathway genes (STIP1, REV1), implicated in human BA via whole exome sequencing, 11 altered biliatresone toxicity in the zebrafish and human cholangiocytes. Finally, we identified pharmacological activators of cGMP signaling as a class of drugs that work synergistically with NAC in attenuating biliatresone-mediated injury by enhancing PQC.…”

Section: Short Summarymentioning

confidence: 79%

“…Whole exome sequencing recently identified potentially deleterious heterozygous variants in genes encoding HSP90 interactors STIP1 and REV1 in two individuals with isolated BA. 11 STIP1 is an evolutionarily conserved co-chaperone of HSP90 and HSP70. 22 REV1 is HSP90 client protein and functions as a Y-family polymerase that plays a central role in translesion DNA synthesis during replication stress.…”

Section: Validation Of Genetic Variants Linked To Hsp90 As Candidate Ba Risk Factorsmentioning

confidence: 99%

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Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia

et al. 2020

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BACKGROUND and AIMS: Extra-hepatic biliary atresia (BA) is a pediatric liver disease with no approved medical therapy. Recent studies using human samples and experimental modeling suggest that glutathione redox metabolism and heterogeneity play a role in disease pathogenesis.We sought to dissect the mechanistic basis of liver redox variation and explore how other stress responses affect cholangiocyte injury in BA. METHODS:We performed quantitative in situ hepatic glutathione redox mapping in zebrafish larvae carrying targeted mutations in glutathione metabolism genes and correlated these findings with sensitivity to the plant-derived BA-linked toxin biliatresone. We also determined whether genetic disruption of HSP90 protein quality control pathway genes implicated in human BA altered biliatresone toxicity in zebrafish and human cholangiocytes. An in vivo screen of a known drug library was performed to identify novel modifiers of cholangiocyte injury in the zebrafish experimental BA model with subsequent validation. RESULTS:Glutathione metabolism gene mutations caused regionally distinct changes in the redox potential of cholangiocytes that differentially sensitized them to biliatresone. Disruption of human BA-implicated HSP90 pathway genes sensitized zebrafish and human cholangiocytes to biliatresone-induced injury independent of glutathione. Phosphodiesterase-5 inhibitors (PDE5i) and other cGMP signaling activators worked synergistically with the glutathione precursor Nacetylcysteine (NAC) in preventing biliatresone-induced injury in zebrafish and human cholangiocytes. PDE5i enhanced proteasomal degradation and required intact HSP90 chaperone. CONCLUSION: Regional variation in glutathione metabolism underlies sensitivity to the biliary toxin biliatresone, and mirrors recently reported BA risk stratification linked to glutathione metabolism gene expression. Human BA can be causatively linked to genetic

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Section: Short Summarymentioning

confidence: 79%

Section: Validation Of Genetic Variants Linked To Hsp90 As Candidate Ba Risk Factorsmentioning

confidence: 99%

Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia

et al. 2020

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“…Intriguingly, inactivation of INVS in mouse model shows a signi cant increase in bilirubin level compared to that of the wild-type, and the pathogenic changes in ductal plate malformation in the intrahepatic biliary of the mutant mouse 51 . However, since then the association of INVS with BA had not been rmly established due to an absence of INVS mutations in patients with BA 52,53 . In fact, INVS mutations have been observed in patients with infantile nephronophthisis type 2 regardless of populations [54][55][56] .…”

Section: Discussionmentioning

confidence: 99%

Novel Findings From Family-based Exome Sequencing for Children With Biliary Atresia

Tran

Dao

et al. 2021

Preprint

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Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree, characterized by the obstruction of bile flow led to liver failure, scarring and cirrhosis. This study aimed to explore the elusive etiology of BA by conducting whole exome sequencing (WES) for 41 children with BA and their parents (35 trios, including one family with two BA diagnosed children and five child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, six de novo and five homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and having a low minor allele frequency against three employed databases: Kinh Vietnamese (KHV), gnomad and 1000 Genome project. Interestingly, AMER1, INVS and OCRL variants were repeatedly found in unrelated probands, and were firstly reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic mutations were unlikely to occur during the morphogenesis. In agreement with earlier attempts, this study implicated a genetical heterogeneity and non-Mendelian inheritance of BA.

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“…Rajagopalan et al . claimed that these mutations were due to exposure to toxic environmental factors [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…STIP1 is a gene that helps the protein transfer response in heat shock response. Rajagopalan et al claimed that these mutations were due to exposure to toxic environ mental factors [25].…”

Section: Gene Number Of Snps Common To 10 Patientsmentioning

confidence: 99%

Whole exome sequencing analysis for mutations in isolated type III biliary atresia patients

Gürünlüoğlu¹,

Koç²,

Durmuş³

et al. 2020

ceh

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Aim of the study: Biliary atresia is an idiopathic, destructive disease that affects both extrahepatic and intrahepatic bile ducts with severe inflammation and manifests as progressive jaundice within the first few months of life. In this study, we aimed to investigate the significance of genetic mutations in the onset of biliary atresia disease. Material and methods: With the approval of the ethics committee and parental consent, blood was taken from patients to obtain their DNA, and the study commenced. In this prospective study, we examined the DNA of 10 patients with no disease other than biliary atresia, and an exome sequence analysis was performed with the new-generation DNA sequencing method. The genetic structure of biliary atresia disease was examined by statistical analysis of the mutations, which were determined according to the reference DNA sequencing. Results: In the exome sequence analysis, the number of mutations detected among the patients changed significantly; the lowest number was 12,591, and the maximum was 19,863. By examining these mutations, we identified the mutated genes that were common to all patients. Conclusions: In this study, the highest mutation rates were detected in the PRIM2 and MAP2K3 genes. These genes have not previously been associated with biliary atresia.

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Exome Sequencing in Individuals with Isolated Biliary Atresia

Cited by 19 publications

References 52 publications

Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia

Impaired Redox and Protein Homeostasis as Risk Factors and Therapeutic Targets in Toxin-Induced Biliary Atresia

Novel Findings From Family-based Exome Sequencing for Children With Biliary Atresia

Whole exome sequencing analysis for mutations in isolated type III biliary atresia patients

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