Portal de Periódicos da CAPES

Artigo Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

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

2022; Nature Portfolio; Volume: 54; Issue: 8 Linguagem: Inglês

10.1038/s41588-022-01120-0

1546-1718

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 Al‐Sannaa, Eissa Faqeih, Majid Alfadhel, Huma Arshad Cheema, Juliette Dupont, Stéphane Bézieau, Bertrand Isidor, Dorrain Yanwen Low, Yulan Wang, Grace Ping Ping Tan, Poh San Lai, Hugues Piloquet, Madeleine Joubert, Hülya Kayserili, Kimberly A. Kripps, Shareef Nahas, Eric P. Wartchow, Mikako Warren, Gandham SriLakshmi Bhavani, Majed Dasouki, Renata Lazari Sandoval, Elisa de 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 Cogné, Aida M. Bertoli‐Avella, Marie Vincent, Katta M. Girisha, Bruno Reversade,

Mitochondrial Function and Pathology

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. Biallelic loss-of-function variants in FOCAD cause a syndromic form of pediatric liver disease by compromising the SKI messenger RNA surveillance pathway.