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Short report
Homozygous variant in TKFC abolishing triokinase activities is associated with isolated immunodeficiency
  1. Camille Tremblay-Laganière1,
  2. Coralie Michaud2,
  3. Raphaël Abourjaili-Bilodeau2,
  4. Alicia Cabezas3,
  5. José Canales3,
  6. María Jesús Costas3,
  7. João M Ribeiro3,
  8. Jessica Leclerc-Blain1,
  9. Fabien Touzot1,
  10. Elie Haddad4,
  11. Pierre Teira1,
  12. Michel Duval1,
  13. Alexandros Onoufriadis5,
  14. Brigitte Meunier6,
  15. José Carlos Cameselle3,
  16. Philippe M Campeau1
  1. 1Department of Pediatrics, CHU Sainte-Justine, Montréal, Québec, Canada
  2. 2Research Centre, CHU Sainte-Justine, Montréal, Québec, Canada
  3. 3Departamento de Bioquímica y Biología Molecular y Genética, Universidad de Extremadura, Badajoz, Spain
  4. 4Pediatrics, University of Montreal, Montréal, Québec, Canada
  5. 5School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
  6. 6Institute for Integrative Biology of the Cell (I2BC), Paris-Saclay University, Gif-sur-Yvette, France
  1. Correspondence to Dr Philippe M Campeau, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada; p.campeau{at}


Background Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants in TKFC are associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs.

Methods Whole-exome sequencing identified a homozygous novel variant in TKFC (c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins.

Results The individual presented with chronic active Epstein-Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient’s immunodeficiency.

Conclusion Our report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further.

  • immunogenetics
  • exome sequencing
  • virus diseases
  • infections

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  • CT-L and CM contributed equally.

  • Contributors CT-L, CM, BM, AO, JCC, JMR and RA-B wrote the manuscript. AC, JC, MJC, BM and JCC performed experiments. JMR and PC made bioinformatic analysis. JL-B, FT, EH, PT and MD provided clinical information and material. AO, BM, JCC, JMR and PC designed the study and interpreted the data.

  • Funding PC is supported by the FRQS and the Canadian Institutes of Health Research (CIHR). The Grupo de Enzimología received support from the Consejería de Economía, Ciencia y Agenda Digital, Junta de Extremadura, Spain with FEDER cofunding (grants IB16066, GR18127 and GR21100).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.