PUBLICATION
Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis
- Authors
- Moreno Traspas, R., Teoh, T.S., Wong, P.M., Maier, M., Chia, C.Y., Lay, K., Ali, N.A., Larson, A., Al Mutairi, F., Al-Sannaa, N.A., Faqeih, E.A., Alfadhel, M., Cheema, H.A., Dupont, J., Bézieau, S., Isidor, B., Low, D.Y., Wang, Y., Tan, G., Lai, P.S., Piloquet, H., Joubert, M., Kayserili, H., Kripps, K.A., Nahas, S.A., Wartchow, E.P., Warren, M., Bhavani, G.S., Dasouki, M., Sandoval, R., Carvalho, E., Ramos, L., Porta, G., Wu, B., Lashkari, H.P., AlSaleem, B., BaAbbad, R.M., Abreu Ferrão, A.N., Karageorgou, V., Ordonez-Herrera, N., Khan, S., Bauer, P., Cogne, B., Bertoli-Avella, A.M., Vincent, M., Girisha, K.M., Reversade, B.
- ID
- ZDB-PUB-220723-2
- Date
- 2022
- Source
- Nature Genetics 54(8): 1214-1226 (Journal)
- Registered Authors
- REVERSADE, Bruno
- Keywords
- none
- MeSH Terms
-
- Adult
- Animals
- Child
- Fibrosis
- Hepatocytes/metabolism
- Humans
- Liver/metabolism
- Liver Cirrhosis*/genetics
- Liver Cirrhosis*/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Tumor Suppressor Proteins/genetics
- Zebrafish*/genetics
- PubMed
- 35864190 Full text @ Nat. Genet.
Citation
Moreno Traspas, R., Teoh, T.S., Wong, P.M., Maier, M., Chia, C.Y., Lay, K., Ali, N.A., Larson, A., Al Mutairi, F., Al-Sannaa, N.A., Faqeih, E.A., Alfadhel, M., Cheema, H.A., Dupont, J., Bézieau, S., Isidor, B., Low, D.Y., Wang, Y., Tan, G., Lai, P.S., Piloquet, H., Joubert, M., Kayserili, H., Kripps, K.A., Nahas, S.A., Wartchow, E.P., Warren, M., Bhavani, G.S., Dasouki, M., Sandoval, R., Carvalho, E., Ramos, L., Porta, G., Wu, B., Lashkari, H.P., AlSaleem, B., BaAbbad, R.M., Abreu Ferrão, A.N., Karageorgou, V., Ordonez-Herrera, N., Khan, S., Bauer, P., Cogne, B., Bertoli-Avella, A.M., Vincent, M., Girisha, K.M., Reversade, B. (2022) Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nature Genetics. 54(8):1214-1226.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping