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

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.

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Fig. 1: Biallelic FOCAD mutations in 14 children diagnosed with pediatric liver disease.
Fig. 2: FOCAD variants are predicted to be loss-of-function alleles.
Fig. 3: focad loss in zebrafish compromises growth, fertility, lifespan and liver homeostasis, phenocopying the human syndrome.
Fig. 4: focad knockout zebrafish livers show altered lipidomic and transcriptomic signatures.
Fig. 5: FOCAD localizes in the cytosol and its absence in patient-derived primary dermal fibroblasts leads to reduced SKIC2 protein levels.
Fig. 6: Loss of FOCAD compromises the stability of the SKI complex, resulting in damaged hepatocytes.

Data availability

RNA-seq data and processed results have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus public repository under accession number GSE168961. Source data are provided with this paper.

Code availability

No custom code was used for data analysis. All software and packages used are listed in the Methods section.

References

  1. Elpek, G. Ö. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J. Gastroenterol. 20, 7260–7276 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Seki, E. & Brenner, D. A. Recent advancement of molecular mechanisms of liver fibrosis. J. Hepatobiliary Pancreat. Sci. 22, 512–518 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  3. Friedman, S. L. Hepatic fibrosis—overview. Toxicology 254, 120–129 (2008).

    CAS  PubMed  Article  Google Scholar 

  4. Ding, B.-S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).

    PubMed  Article  CAS  Google Scholar 

  5. Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).

    PubMed  Article  CAS  Google Scholar 

  6. Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Schuppan, D. & Afdhal, N. H. Liver cirrhosis. Lancet 371, 838–851 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Mokdad, A. A. et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 12, 145 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  9. Asrani, S. K., Devarbhavi, H., Eaton, J. & Kamath, P. S. Burden of liver diseases in the world. J. Hepatol. 70, 151–171 (2019).

    PubMed  Article  Google Scholar 

  10. Yoshiji, H. et al. Evidence-based clinical practice guidelines for liver cirrhosis 2020. Hepatol. Res. 51, 725–749 (2021).

    PubMed  Article  Google Scholar 

  11. Brockschmidt, A. et al. KIAA1797/FOCAD encodes a novel focal adhesion protein with tumour suppressor function in gliomas. Brain 135, 1027–1041 (2012).

    PubMed  Article  Google Scholar 

  12. Brand, F. et al. FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas. Acta Neuropathol. 139, 175–192 (2020).

    CAS  PubMed  Article  Google Scholar 

  13. Weren, R. D. A. et al. Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development. J. Pathol. 236, 155–164 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Wiech, T. et al. Genome-wide analysis of genetic alterations in Barrett’s adenocarcinoma using single nucleotide polymorphism arrays. Lab. Invest. 89, 385–397 (2009).

    CAS  PubMed  Article  Google Scholar 

  15. Toh-E, A., Guerry, P. & Wickner, R. B. Chromosomal superkiller mutants of Saccharomyces cerevisiae. J. Bacteriol. 136, 1002–1007 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Brown, J. T., Bai, X. & Johnson, A. W. The yeast antiviral proteins Ski2p, Ski3p, and Ski8p exist as a complex in vivo. RNA 6, 449–457 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Widner, W. R. & Wickner, R. B. Evidence that the SKI antiviral system of Saccharomyces cerevisiae acts by blocking expression of viral mRNA. Mol. Cell. Biol. 13, 4331–4341 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Synowsky, S. A. & Heck, A. J. R. The yeast Ski complex is a hetero-tetramer. Protein Sci. 17, 119–125 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Halbach, F., Reichelt, P., Rode, M. & Conti, E. The yeast Ski complex: crystal structure and RNA channeling to the exosome complex. Cell 154, 814–826 (2013).

    CAS  PubMed  Article  Google Scholar 

  20. Anderson, J. S. & Parker, R. P. The 3′ to 5′ degradation of yeast mRNAs is a general mechanism for mRNA turnover that requires the SKI2 DEVH box protein and 3′ to 5′ exonucleases of the exosome complex. EMBO J. 17, 1497–1506 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Tuck, A. C. et al. Mammalian RNA decay pathways are highly specialized and widely linked to translation. Molecular Cell 77, 1222–1236.e13 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Lee, W. S. & Sokol, R. J. Mitochondrial hepatopathies: advances in genetics and pathogenesis. Hepatology 45, 1555–1565 (2007).

    CAS  PubMed  Article  Google Scholar 

  23. Fabris, L. et al. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat. Rev. Gastroenterol. Hepatol. 16, 497–511 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  24. Ozen, H. Glycogen storage diseases: new perspectives. World J. Gastroenterol. 13, 2541–2553 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Lange, H. et al. RST1 and RIPR connect the cytosolic RNA exosome to the Ski complex in Arabidopsis. Nat. Commun. 10, 3871 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Desmet, F.-O. et al. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 37, e67 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Schwabe, R. F. & Maher, J. J. Lipids in liver disease: looking beyond steatosis. Gastroenterology 142, 8–11 (2012).

    PubMed  Article  Google Scholar 

  29. Ding, H., Wang, J., Ren, H. & Shi, X. Lipometabolism and glycometabolism in liver diseases. BioMed Res. Int. 2018, 1287127 (2018).

    PubMed  PubMed Central  Google Scholar 

  30. Uhlar, C. M. & Whitehead, A. S. Serum amyloid A, the major vertebrate acute-phase reactant. Eur. J. Biochem. 265, 501–523 (1999).

    CAS  PubMed  Article  Google Scholar 

  31. Aly, H. H. et al. RNA exosome complex regulates stability of the hepatitis B virus X-mRNA transcript in a non-stop-mediated (NSD) RNA quality control mechanism. J. Biol. Chem. 291, 15958–15974 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Zhu, B. et al. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 19, 1668–1673 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Qu, X. et al. The human DEVH-box protein Ski2w from the HLA is localized in nucleoli and ribosomes. Nucleic Acids Res. 26, 4068–4077 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Xu, L. et al. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut 54, 142–151 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Waki, K. et al. Establishment of functional telomerase immortalized human hepatocytes and a hepatic stellate cell line for telomere-targeting anticancer drug development. Cancer Sci. 101, 1678–1685 (2010).

    CAS  PubMed  Article  Google Scholar 

  36. Border, W. A. & Noble, N. A. Transforming growth factor beta in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

    CAS  PubMed  Article  Google Scholar 

  37. Junge, N., Sharma, A. D. & Ott, M. About cytokeratin 19 and the drivers of liver regeneration. J. Hepatol. 68, 5–7 (2018).

    Article  Google Scholar 

  38. Yoneda, N. et al. Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma. Lab. Invest. 91, 262–272 (2011).

    CAS  PubMed  Article  Google Scholar 

  39. Chen, J. et al. Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension. Sci. Rep. 10, 15558 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Xu, Y. et al. Lipocalin-2 protects against diet-induced nonalcoholic fatty liver disease by targeting hepatocytes. Hepatol. Commun. 3, 763–775 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Mungrue, I. N., Pagnon, J., Kohannim, O., Gargalovic, P. S. & Lusis, A. J. CHAC1/MGC4504 is a novel proapoptotic component of the unfolded protein response, downstream of the ATF4-ATF3-CHOP cascade. J. Immunol. 182, 466–476 (2009).

    CAS  PubMed  Article  Google Scholar 

  42. Magne, L. et al. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J. Hepatol. 54, 729–737 (2011).

    CAS  PubMed  Article  Google Scholar 

  43. Henriksen, J. H. et al. Dynamics of albumin in plasma and ascitic fluid in patients with cirrhosis. J. Hepatol. 34, 53–60 (2001).

    CAS  PubMed  Article  Google Scholar 

  44. Feldmann, G., Penaud-Laurencin, J., Crassous, J. & Benhamou, J. P. Albumin synthesis by human liver cells: its morphological demonstration. Gastroenterology 63, 1036–1048 (1972).

    CAS  PubMed  Article  Google Scholar 

  45. Boon, R. et al. Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines. Nat. Commun. 11, 1393 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Villeneuve, J.-P. & Pichette, V. Cytochrome P450 and liver diseases. Curr. Drug Metab. 5, 273–282 (2004).

    CAS  PubMed  Article  Google Scholar 

  47. Siegel, R. C., Chen, K. H., Greenspan, J. S. & Aguiar, J. M. Biochemical and immunochemical study of lysyl oxidase in experimental hepatic fibrosis in the rat. Proc. Natl Acad. Sci. USA 75, 2945–2949 (1978).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Vadasz, Z. et al. Abnormal deposition of collagen around hepatocytes in Wilson’s disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J. Hepatol. 43, 499–507 (2005).

    CAS  PubMed  Article  Google Scholar 

  49. Mandrekar, P., Ambade, A., Lim, A., Szabo, G. & Catalano, D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 54, 2185–2197 (2011).

    CAS  PubMed  Article  Google Scholar 

  50. Kobayashi, K. et al. Role of monocyte chemoattractant protein-1 in liver fibrosis with transient myeloproliferative disorder in down syndrome. Hepatol. Commun. 2, 230–236 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Xie, J. et al. Macrophage migration inhibitor factor upregulates MCP-1 expression in an autocrine manner in hepatocytes during acute mouse liver injury. Sci. Rep. 6, 27665 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Li, S. et al. TSLP protects against liver I/R injury via activation of the PI3K/Akt pathway. JCI Insight 4, e129013 (2019).

    PubMed Central  Article  Google Scholar 

  53. Sawa, Y. et al. Hepatic interleukin-7 expression regulates T cell responses. Immunity 30, 447–457 (2009).

    CAS  PubMed  Article  Google Scholar 

  54. Affò, S. et al. CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis. Gut 63, 1782–1792 (2014).

    PubMed  Article  CAS  Google Scholar 

  55. Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Esmaili, S. et al. Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner. Cell Systems 12, 432–445.e7 (2021).

    CAS  PubMed  Article  Google Scholar 

  57. Bourgeois, P. et al. Tricho-hepato-enteric syndrome mutation update: mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects. Hum. Mutat. 39, 774–789 (2018).

    CAS  PubMed  Article  Google Scholar 

  58. Hartley, J. L. et al. Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). Gastroenterology 138, 2388–2398 (2010). 2398.e1–2.

    CAS  PubMed  Article  Google Scholar 

  59. Hiejima, E. et al. Tricho-hepato-enteric syndrome with novel SKIV2L gene mutations: a case report. Medicine (Baltimore) 96, e8601 (2017).

    Article  Google Scholar 

  60. Fabre, A. et al. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. Am. J. Hum. Genet. 90, 689–692 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Sinha, N. K. et al. EDF1 coordinates cellular responses to ribosome collisions. eLife 9, e58828 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Wu, C. C.-C., Peterson, A., Zinshteyn, B., Regot, S. & Green, R. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416.e14 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Queck, A. et al. Systemic MCP-1 levels derive mainly from injured liver and are associated with complications in cirrhosis. Front. Immunol. 11, 354 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Ambade, A. et al. Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis, and inflammation in mice. Hepatology 69, 1105–1121 (2019).

    CAS  PubMed  Article  Google Scholar 

  65. Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012).

    CAS  PubMed  Article  Google Scholar 

  66. Teng, K.-Y. et al. Blocking the CCL2-CCR2 axis using CCL2 neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol. Cancer Ther. 16, 312–322 (2017).

    CAS  PubMed  Article  Google Scholar 

  67. Anstee, Q. M. et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design. Contemp. Clin. Trials 89, 105922 (2020).

    PubMed  Article  Google Scholar 

  68. Clark, M. M. et al. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. Sci. Transl. Med. 11, eaat6177 (2019).

    PubMed  Article  CAS  Google Scholar 

  69. Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    CAS  PubMed  Article  Google Scholar 

  70. Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Schwarz, J. M., Rödelsperger, C., Schuelke, M. & Seelow, D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat. Methods 7, 575–576 (2010).

    CAS  PubMed  Article  Google Scholar 

  72. Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886–D894 (2019).

    CAS  PubMed  Article  Google Scholar 

  73. Quang, D., Chen, Y. & Xie, X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 31, 761–763 (2015).

    CAS  PubMed  Article  Google Scholar 

  74. Shamsani, J. et al. A plugin for the ensembl variant effect predictor that uses MaxEntScan to predict variant spliceogenicity. Bioinformatics 35, 2315–2317 (2019).

    CAS  PubMed  Article  Google Scholar 

  75. Pertea, M., Lin, X. & Salzberg, S. L. GeneSplicer: a new computational method for splice site prediction. Nucleic Acids Res. 29, 1185–1190 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  77. Vangipuram, M., Ting, D., Kim, S., Diaz, R. & Schüle, B. Skin punch biopsy explant culture for derivation of primary human fibroblasts. J. Vis. Exp. 77, e3779 (2013).

    Google Scholar 

  78. Tang, W. J. Blot-affinity purification of antibodies. Methods Cell. Biol. 37, 95–104 (1993).

    CAS  PubMed  Article  Google Scholar 

  79. Jao, L.-E., Wente, S. R. & Chen, W. Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc. Natl Acad. Sci. USA 110, 13904–13909 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We are grateful to the families of affected individuals for their participation and kind cooperation in this study. We are also grateful to all members of the Reversade laboratory for constructive discussions and suggestions. We thank R. Weber (Hannover Medical School, Germany) for providing the FOCAD expression construct used for our transient transfections, as well as A. van Hoof (University of Texas Health Science Center at Houston, Texas, USA) and J. Mendell (University of Texas Southwestern Medical Center, Texas, USA) for their insights on the biology of the SKI complex. M.M. was supported by a Career Development Award (CDF Project NR C210812055) from the A*STAR, Biomedical Research Council (Singapore). K.M.G. was supported by the Clinical Research Center grant (IA/CRC/20/1/600002) from India Alliance (India). The authors also thank the King Fahad Medical City Research Center (Saudi Arabia) for the partial support to E.A.F. (grant no. 019-052). B.R. is a fellow of the Branco Weiss Foundation (Switzerland) and the National Research Foundation (Singapore), and an A*STAR and EMBO Young Investigator. This work was also supported by an inaugural Use-Inspired Basic Research (UIBR) central fund and a Brain-Body Initiative (BBI) grant in Neurometabolism to B.R. from the Agency for Science, Technology and Research (A*STAR) in Singapore.

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Contributions

B.R., K.M.G., M.V. and B.C. initiated the study. B.R. and R.M.T. designed the study. B.R. and P.-M.W. supervised the study. B.R., P.B., A.M.B.-A., V.K., N.O.-H., S.K., M.A. and H.K. coordinated the clinical part of the study. K.M.G., M.V., B.C., A.L., F.A.M., N.A.A.-S., E.A.F., H.A.C., J.D., S.B., B.I., H.P., M.J., K.A.K., S.A.N., E.P.W., M.W., G.S.B., M.D., R.S., E.C., L.R., G.P., H.P.L., B.A., R.M.B. and A.N.A.F. conducted the clinical and genetic evaluation of the patients, the collection of human biological samples and the trio whole genome/exome sequencing for the corresponding affected family. R.M.T. designed and performed all the biochemical, cell culture and in vivo experiments, with help from B.R., T.S.T., P.-M.W., M.M., K.L., N.A.A. and C.Y.C. D.Y.L. and Y.W. conducted the lipidomics analysis on zebrafish livers. G.T. and P.S.L. conducted the clinical curation of the FOCAD variants. B.W. performed the structural analysis of the missense FOCAD variants. R.M.T. conducted all the rest of the data processing and analysis. B.R. and R.M.T. wrote the manuscript with input from all co-authors and performed all revisions.

Corresponding authors

Correspondence to Ricardo Moreno Traspas or Bruno Reversade.

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Competing interests

P.B., A.M.B.-A., V.K., N.O.-H. and S.K. are employed by and receive a salary from Centogene AG (exome sequencing is among the commercially available tests). K.M.G. is founder and director of Suma Genomics (exome sequencing is among the commercially available tests). The remaining authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Clinical data from patient F2-II:2 (France).

a, Photograph of the patient showing a triangular face, high forehead and plagiocephaly. b, Liver biopsy at 2 years and 4 months. Periodic acid Schiff staining (PAS, top left) showed elevated intrahepatocellular glycogen. Gordon and Sweet’s silver staining (bottom left) revealed some regions of the liver parenchyma with an abnormal reticular fiber pattern (yellow arrows). H&E staining (top middle and right) showed presence of fibrogenic connective tissue (black frame) and lipid vesicles in hepatocytes indicative of steatosis (green arrows). Picrosirius red staining (bottom middle and right) confirmed the presence of fibrotic bands (black frame) and highlighted the presence of pericellular collagen fibers among hepatocytes (white arrows). Scale bars, 50 μm (bottom left) and 25 μm (bottom right).

Extended Data Fig. 2 focad is maternally contributed in zebrafish.

a, Schematic diagram of the genomic structure of focad in zebrafish. Two germline deletion mutations were selected to generate focad knockouts using CRISPR-Cas9 technology. The focad gene comprises 44 exons (bars). The blue line highlights the region targeted by the CRISPR guide RNA (gRNA) in exon 4. Black arrows point where the genomic deletions of 7 (focadΔ7) and 8 (focadΔ8) base pairs have occurred, which result in out-of-frame alleles creating early stop codons. b, Temporal RT-qPCR quantification of the expression levels of focad relative to β-actin during the 7 days postfertilization. focad is maternally contributed to the egg. Data are presented as mean ± s.e.m. (n = 2 biological replicates of 30 to 50 embryos).

Extended Data Fig. 3 Overlap of the main clinical manifestations seen in FOCAD-deficient patients and THES type 1 and type 2.

Data related to both types of THES were extracted from Bourgeois et al.57.

Supplementary information

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Unprocessed western blots.

Source Data Fig. 5

Unprocessed western blots.

Source Data Fig. 6

Unprocessed western blots.

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Moreno Traspas, R., Teoh, T.S., Wong, PM. et al. Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nat Genet 54, 1214–1226 (2022). https://doi.org/10.1038/s41588-022-01120-0

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