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 Lai; Hugues Piloquet; Madeleine Joubert; Hulya Kayserili; Kimberly A Kripps; Shareef A Nahas; Eric P Wartchow; Mikako Warren; Gandham SriLakshmi 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

doi:10.1038/s41588-022-01120-0

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

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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, …

Nature genetics, Vol.54(8), pp.1214-1226

01/08/2022

DOI: https://doi.org/10.1038/s41588-022-01120-0

PMID: 35864190

Résumé

Adult

Animals

Child

Hepatocytes - metabolism

Humans

Liver - metabolism

Liver Cirrhosis - genetics

Liver Cirrhosis - metabolism

RNA, Messenger - genetics

RNA, Messenger - metabolism

Syndrome

Tumor Suppressor Proteins - genetics

Zebrafish - genetics

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.

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Détails

Titre: Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis
Créateurs - sans rôle: Ricardo Moreno Traspas - Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. ricardo.traspas@reversade.com
Tze Shin Teoh - Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Pui-Mun Wong - Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore, ASTAR, Singapore, Singapore
Michael Maier - Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore, ASTAR, Singapore, Singapore
Crystal Y Chia - Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore, ASTAR, Singapore, Singapore
Kenneth Lay - Genome Institute of Singapore
Nur Ain Ali - Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore, ASTAR, Singapore, Singapore
Austin Larson - Children's Hospital Colorado
Fuad Al Mutairi - College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
Nouriya Abbas Al-Sannaa - Pediatric Services, John Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
Eissa Ali Faqeih - Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Majid Alfadhel - Department of Medical Genomic Research, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
Huma Arshad Cheema - Division of Pediatric Gastroenterology-Hepatology and Nutrition, The Children's Hospital and The Institute of Child Health, Lahore, Pakistan
Juliette Dupont - Department of Pediatrics, Genetic Services, Lisbon North University Hospital Center, Lisbon, Portugal
Stéphane Bézieau - Medical Genetics Service, Nantes University Hospital Center, Nantes, France
Bertrand Isidor - Medical Genetics Service, Nantes University Hospital Center, Nantes, France
Dorrain Yanwen Low - Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Yulan Wang - Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
Grace Tan - Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Poh San Lai - Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Hugues Piloquet - Gastropediatrics Department, Nantes University Hospital Center, Nantes, France
Madeleine Joubert - Anatomopathology Department, Nantes University Hospital Center, Nantes, France
Hulya Kayserili - Koç University
Kimberly A Kripps - Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Shareef A Nahas - Rady Children's Institute for Genomic Medicine, San Diego, CA, USA
Eric P Wartchow - Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO, USA
Mikako Warren - Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
Gandham SriLakshmi Bhavani - Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
Majed Dasouki - Department of Pediatric Genetics, AdventHealth Medical Group, Orlando, FL, USA
Renata Sandoval - Department of Oncogenetics, Hospital Sírio-Libanês, Brasília, Brazil
Elisa Carvalho - Department of Pediatric Gastroenterology and Hepatology, Hospital da Criança de Brasília José Alencar, UniCEUB, Brasília, Brazil
Luiza Ramos - Mendelics Genomic Analysis, São Paulo, Brazil
Gilda Porta - Department of Pediatric Hepatology, Transplant Unit, Hospital Sírio-Libanês, São Paulo, Brazil
Bin Wu - Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore
Harsha Prasada Lashkari - Manipal Academy of Higher Education, Manipal, India
Badr AlSaleem - Section of Pediatric Gastroenterology-Hepatology, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Raeda M BaAbbad - Section of Pediatric Gastroenterology-Hepatology, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia
Anabela Natália Abreu Ferrão - Department of Pediatrics, Hematology Unit, Lisbon North University Hospital Center, Lisbon, Portugal
Vasiliki Karageorgou - Centogene AG, Rostock, Germany
Natalia Ordonez-Herrera - Centogene AG, Rostock, Germany
Suliman Khan - Centogene
Peter Bauer - Centogene AG, Rostock, Germany
Benjamin Cogne - Medical Genetics Service, Nantes University Hospital Center, Nantes, France
Aida M Bertoli-Avella - Centogene AG, Rostock, Germany
Marie Vincent - Medical Genetics Service, Nantes University Hospital Center, Nantes, France
Katta Mohan Girisha - Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
Bruno Reversade - Smart-Health Initiative, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia. bruno@reversade.com
Détails de publication: Nature genetics, Vol.54(8), pp.1214-1226
Note de subvention: IA/CRC/20/1/600002 / DBT-Wellcome Trust India Alliance
Identifiants: 99158859609311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article