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Antibody Deficiency in Patients with Biallelic KARS1 Mutations

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An Author Correction to this article was published on 03 November 2023

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Abstract

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

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Acknowledgements

We thank all the patients and family members that participated in the study.

Author information

Authors and Affiliations

  1. Centro Tettamanti, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy

    Francesco Saettini, Grazia Fazio, Cristina Bugarin, Manuel Quadri, Gianni Cazzaniga & Andrea Biondi

  2. Pediatria, Fondazione IRCCS San Gerardo Dei Tintori, Monza, Italy

    Fabiola Guerra, Serena Gasperini & Andrea Biondi

  3. Dipartimento Di Medicina E Chirurgia, Università Degli Studi Milano-Bicocca, Milan, Italy

    Fabiola Guerra, Mario Mauri, Gianni Cazzaniga & Andrea Biondi

  4. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada

    Hugh J McMillan

  5. Department of Clinical Genomics & Pediatrics, Saitama Medical University, Moroyama, Saitama, Japan

    Akira Ohtake

  6. Child Neurology, “Fondazione IRCCS IstitutoNeurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy

    Anna Ardissone

  7. Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Kodaira, Japan

    Masayuki Itoh

  8. Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy

    Sabrina Giglio

  9. Department of Translational Medical Sciences, Section of Pediatrics, Federico II University of Naples, Naples, Italy

    Gerarda Cappuccio, Giuliana Giardino & Roberta Romano

  10. Current address: Baylor College of Medicine, Houston, TX, USA

    Gerarda Cappuccio

  11. Flow Cytometry Unit, Clinical ChemistryLaboratory, ASST Spedali Civili, Brescia, Italy

    Daniele Moratto & Marco Chiarini

  12. Center for Postgraduate Education and Training, National Center for Child Health and Development (NCCHD), Tokyo, Japan

    Ishiguro Akira

  13. Division of Hematology, National Center for Child Health and Development (NCCHD), Tokyo, Japan

    Ishiguro Akira

  14. Division of Medical Genetics, National Center for Child Health and Development, Tokyo, Japan

    Yasuyuki Fukuhara

  15. Division of Neurology, National Center for Child Health and Development (NCCHD), Tokyo, Japan

    Itaru Hayakawa & Yasushi Okazaki

  16. Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan

    Yasushi Okazaki

  17. Ematologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

    Rocco Piazza

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  1. Francesco Saettini
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Contributions

Francesco Saettini designed the work and coordinated the project. Mario Mauri, Grazia Fazio, Manuel Quadri, and Crisitina Bugaring performed the experiments. Francesco Saettini wrote the manuscript. All authors contributed with clinical, immunological, and molecular data. All authors approved the final version of the manuscript.

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Correspondence to Francesco Saettini.

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The study was approved from the local hospital Ethical Committee and was conducted in accordance with the 1964 Helsinki Declaration.

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Saettini, F., Guerra, F., Fazio, G. et al. Antibody Deficiency in Patients with Biallelic KARS1 Mutations. J Clin Immunol 43, 2115–2125 (2023). https://doi.org/10.1007/s10875-023-01584-7

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