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Atypical immune phenotype in severe combined immunodeficiency patients with novel mutations in IL2RG and JAK3

Genes & Immunity volume 21, pages 326–334 (2020)Cite this article

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Abstract

Mutations in the common gamma chain of the interleukin 2 receptor (IL2RG) or the associated downstream signaling enzyme Janus kinase 3 (JAK3) genes are typically characterized by a T cell-negative, B cell-positive, natural killer (NK) cell-negative (T−B+NK−) severe combined immunodeficiency (SCID) immune phenotype. We report clinical course, immunological, genetic and proteomic work-up of two patients with different novel mutations in the IL-2-JAK3 pathway with a rare atypical presentation of T−B+NK− SCID. Lymphocyte subpopulation revealed significant T cells lymphopenia, normal B cells, and NK cells counts (T−B+NK+SCID). Despite the presence of B cells, IgG levels were low and IgA and IgM levels were undetectable. T-cell proliferation in response to mitogens in patient 1 was very low and T-cell receptor V-beta chain repertoire in patient 2 was polyclonal. Whole-exome sequencing revealed novel mutations in both patients (patient 1—c.923delC frame-shift mutation in the IL2RG gene, patient 2—c.G172A a homozygous missense mutation in the JAK3 gene). Bioinformatic analysis of the JAK3 mutation indicated deleterious effect and 3D protein modeling located the mutation to a surface exposed alpha-helix structure. Our findings help to link between genotype and phenotype, which is a key factor for the diagnosis and treatment of SCID patients.

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Fig. 1: T-SCID mutations.
Fig. 2: Variable segment usage for T-cell receptor β.
Fig. 3: Protein predict analysis results.
Fig. 4: Structural model of JAK3 N-terminal domain.

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Authors and Affiliations

  1. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Lior Goldberg, Tali Stauber & Raz Somech

  2. Pediatric Department A, Pediatric Immunology Service, Jeffrey Modell Foundation (JMF) Center, Sheba Medical Center, Tel HaShomer, Israel

    Lior Goldberg, Amos J. Simon, Atar Lev, Tali Stauber & Raz Somech

  3. Sheba Cancer Research Center, Sheba Medical Center, Tel HaShomer, Israel

    Amos J. Simon, Ortal Barel & Gideon Rechavi

  4. The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel HaShomer, Israel

    Ortal Barel & Gideon Rechavi

  5. Bioinformatics Consulting, Gat Rimon, Israel

    Vered Kunik

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Correspondence to Raz Somech.

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Goldberg, L., Simon, A.J., Lev, A. et al. Atypical immune phenotype in severe combined immunodeficiency patients with novel mutations in IL2RG and JAK3. Genes Immun 21, 326–334 (2020). https://doi.org/10.1038/s41435-020-00111-7

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