Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/229564
Title: LOSS OF FOCAD, OPERATING IN THE SKI mRNA SURVEILLANCE PATHWAY, IS RESPONSIBLE FOR A SYNDROMIC FORM OF PEDIATRIC LIVER CIRRHOSIS
Authors: RICARDO MORENO TRASPAS
ORCID iD:   orcid.org/0000-0003-2607-107X
Keywords: FOCAD, SKI complex, mRNA surveillance, liver, cirrhosis, zebrafish
Issue Date: 12-Jan-2022
Citation: RICARDO MORENO TRASPAS (2022-01-12). LOSS OF FOCAD, OPERATING IN THE SKI mRNA SURVEILLANCE PATHWAY, IS RESPONSIBLE FOR A SYNDROMIC FORM OF PEDIATRIC LIVER CIRRHOSIS. ScholarBank@NUS Repository.
Abstract: Cirrhosis is usually a late onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its aetiology in infants is much less understood. In this study we report 14 children from 10 unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, recessive variants in FOCAD were found to segregate with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered mRNA degradation processes in the liver. Using patient's primary cells and CRISPR/Cas9-mediated inactivation in human hepatic cell lines, we find that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIV2L and its cofactor TTC37. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signalling axis.
URI: https://scholarbank.nus.edu.sg/handle/10635/229564
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