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Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Genes & Immunity volume 12, pages 434–444 (2011)Cite this article

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Abstract

Artemis deficiency is known to result in classical T−B− severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T−B− SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5′ splice-site or an intronic point mutation creating a novel 3′ splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3′ splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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Acknowledgements

We thank Dr A Aartsma-Rus for support with the AON design, WM Comans-Bitter and S de Bruin-Versteeg for making the figures and L Du and MA Berkowska for support with analyzing the switch junctions. This work was supported by grants from the foundation ‘Sophia Kinderziekenhuis Fonds’ (grant 589 H IJspeert and M van der Burg).

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Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    H IJspeert, M C van Zelm, J J M van Dongen & M van der Burg

  2. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    H IJspeert

  3. Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

    A C Lankester & M J D van Tol

  4. Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    J M van den Berg

  5. Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands

    W Wiegant & A Pastink

  6. Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    C M R Weemaes & A Warris

  7. Department of Laboratory Medicine, Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden

    Q Pan-Hammarström

  8. Department of Cell biology and Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    D C van Gent

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  1. H IJspeert
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Correspondence to M van der Burg.

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IJspeert, H., Lankester, A., van den Berg, J. et al. Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes Immun 12, 434–444 (2011). https://doi.org/10.1038/gene.2011.16

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