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A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis

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Abstract

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/β, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.

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Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank the patient and their family for participating in our research. We thank the interdisciplinary medical personnel involved in the care of the patient and his family.

Funding

This work was supported by the McGill University Health Centre – Foundation via the SDR Project.

D.C. Vinh is supported by the Fonds de Recherche du Québec—Santé (FRQS) – Senior clinician-scientist scholar program.

Author information

Author notes

  1. Lucie Roussel and Anne Pham-Huy contributed equally to this work.

Authors and Affiliations

  1. Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada

    Lucie Roussel, Anna Perez, Guillaume Bourdel, Yichun Sun, Stephanya Tellez Villavicencio, Stéphane Bernier, Yongbiao Li, Makayla Kazimerczak-Brunet, Rolan Alattar, Marc-André Déry & Donald C. Vinh

  2. Division of Infectious Diseases, Immunology and Allergy, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Anne Pham-Huy & Justin Penner

  3. Division of Metabolics and Newborn Screening, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Andrea C. Yu

  4. Division of Neurology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    Sunita Venkateswaran

  5. Division of Respirology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada

    Adam J. Shapiro

  6. Department of Pediatrics, Qikiqtani General Hospital, Iqaluit, NT, Canada

    Justin Penner

  7. Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada

    Donald C. Vinh

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  1. Lucie Roussel
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Contributions

Study design and supervision were performed by Lucie Roussel, Anne Pham-Huy, and Donald C. Vinh. Clinical data generation, acquisition, and analysis were performed by Anne Pham-Huy, Andrea C. Yu, Sunita Venkateswaran, and Justin Penner. Experimental data was done by Lucie Roussel, Anna Perez, Guillaume Bourdel, Yichun Sun, Stephanya Tellez Villavicencio, Stéphane Bernier, Yongbiao Li, Makayla Kazimerczak-Brunet, Rolan Alattar, Marc-André Déry, and Adam J. Shapiro. Lucie Roussel, Anne Pham-Huy, and Donald C. Vinh wrote the first draft of the manuscript. All authors have reviewed, contributed to, and approved the final version of the manuscript. Donald C. Vinh is the principal investigator providing supervision and funding.

Corresponding author

Correspondence to Donald C. Vinh.

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Ethics Approval

The Research Ethics Board of the Research Institute – McGill University Health Centre has approved this research (No. 2021–6624).

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The authors confirm that a relevant local consent has been signed by the patient and/or the legally authorized representative.

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Competing Interests

D.C. Vinh has received research support, unrestricted educational grants, consultancy fees, and speaker honoraria from CSL Behring; has received consultancy fees from AstraZeneca, Moderna, and Takeda; and has undertaken clinical trials for Cidara Therapeutics and Moderna. The remaining authors declare no competing interests.

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Roussel, L., Pham-Huy, A., Yu, A.C. et al. A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis. J Clin Immunol 43, 2011–2021 (2023). https://doi.org/10.1007/s10875-023-01580-x

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