Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis

Ricardo Moreno Traspas, Tze Shin Teoh, Pui Mun Wong, Michael Maier, Crystal Y. Chia, Kenneth Lay, Nur Ain Ali, Austin Larson, Fuad Al Mutairi, Nouriya Abbas Al-Sannaa, Eissa Ali Faqeih, Majid Alfadhel, Huma Arshad Cheema, Juliette Dupont, Stéphane Bézieau, Bertrand Isidor, Dorrain Yanwen Low, Yulan Wang, Grace Tan, Poh San LaiHugues Piloquet, Madeleine Joubert, Hulya Kayserili, Kimberly A. Kripps, Shareef A. Nahas, Eric P. Wartchow, Mikako Warren, Gandham Sri Lakshmi Bhavani, Majed Dasouki, Renata Sandoval, Elisa Carvalho, Luiza Ramos, Gilda Porta, Bin Wu, Harsha Prasada Lashkari, Badr AlSaleem, Raeda M. BaAbbad, Anabela Natália Abreu Ferrão, Vasiliki Karageorgou, Natalia Ordonez-Herrera, Suliman Khan, Peter Bauer, Benjamin Cogne, Aida M. Bertoli-Avella, Marie Vincent, Katta Mohan Girisha, Bruno Reversade

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient’s primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. 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 signaling axis.

Original languageEnglish (US)
Pages (from-to)1214-1226
Number of pages13
JournalNature genetics
Volume54
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • Genetics

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