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

• Published in: Nature genetics Vol. 54; no. 8; pp. 1214 - 1226
• Main Authors: Moreno Traspas, Ricardo, Teoh, Tze Shin, Wong, Pui-Mun, Maier, Michael, Chia, Crystal Y., Lay, Kenneth, Ali, Nur Ain, Larson, Austin, Al Mutairi, Fuad, Al-Sannaa, Nouriya Abbas, Faqeih, Eissa Ali, Alfadhel, Majid, Cheema, Huma Arshad, Dupont, Juliette, Bézieau, Stéphane, Isidor, Bertrand, Low, Dorrain Yanwen, Wang, Yulan, Tan, Grace, Lai, Poh San, Piloquet, Hugues, Joubert, Madeleine, Kayserili, Hulya, Kripps, Kimberly A., Nahas, Shareef A., Wartchow, Eric P., Warren, Mikako, Bhavani, Gandham SriLakshmi, Dasouki, Majed, Sandoval, Renata, Carvalho, Elisa, Ramos, Luiza, Porta, Gilda, Wu, Bin, Lashkari, Harsha Prasada, AlSaleem, Badr, BaAbbad, Raeda M., Abreu Ferrão, Anabela Natália, Karageorgou, Vasiliki, Ordonez-Herrera, Natalia, Khan, Suliman, Bauer, Peter, Cogne, Benjamin, Bertoli-Avella, Aida M., Vincent, Marie, Girisha, Katta Mohan, Reversade, Bruno
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2022; Nature Publishing Group
• Subjects: 631/208/191/2018; 692/308/2056; 692/699/1503/1607/1604; Adult; Agriculture; Albumins; Alcoholism; Animal Genetics and Genomics; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; CCR2 protein; Cell cycle; Cell lines; Child; Cirrhosis; Congenital diseases; CRISPR; Etiology; Families & family life; Gene Function; Gene sequencing; Genomes; Hepatitis; Hepatocytes; Hepatocytes - metabolism; Hernias; Homeostasis; Human Genetics; Humans; Hypertension; Inactivation; Liver; Liver - metabolism; Liver cirrhosis; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver diseases; Metabolism; Monocyte chemoattractant protein 1; mRNA; Mutation; Patients; Pediatrics; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Surveillance; Syndrome; Transplants & implants; Tumor Suppressor Proteins - genetics; Viral infections; Zebrafish; Zebrafish - genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-022-01120-0

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.