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Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire

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Abstract

MALT1 (mucosa-associated lymphoid tissue lymphoma-translocation gene 1) is an intracellular signaling protein that activates NFκB and is crucial for both the adaptive and innate immune responses. Only 6 patients with immune deficiencies secondary to inherited mutations in the MALT1 gene have been described.

Purpose

To provide clinical and immunological insights from 2 patients diagnosed with MALT1 immunodeficiency syndrome due to a novel MALT1 mutation.

Methods

Two cousins with suspected combined immunodeficiency underwent immunological and genetic work-up, including lymphocyte phenotyping, lymphocyte activation by mitogen stimulation, and next-generation sequencing (NGS) of T cell receptor gamma chain (TRG) repertoire. Whole exome sequencing was performed to identify the underlying genetic defect.

Results

Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity. Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells. A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3. TRG repertoire was diverse with a clonal expansion pattern. Genetic analysis identified a novel autosomal recessive homozygous c.1799T>A; p. I600N missense mutation in MALT1. MALT1 protein expression was markedly reduced, and in vitro IL-2 production and NFκB signaling pathway were significantly impaired.

Conclusions

Two patients harboring a novel MALT1 mutation presented with signs of immune deficiency and dysregulation and were found to have an abnormal T cell receptor repertoire. These findings reinforce the link between MALT1 deficiency and combined immunodeficiency. Early diagnosis is crucial, and curative treatment by hematopoietic stem cell transplantation may be warranted.

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Abbreviations

CBM:

CARD9/10/11-BCL10-MALT1

CID:

combined immunodeficiency

HSCT:

hematopoietic stem cell transplantation

MALT-1:

mucosa-associated lymphoid tissue lymphoma-translocation gene 1

NGS:

next-generation sequencing

PBMCs:

peripheral blood mononuclear cells

SCID:

severe combined immunodeficiency

TRECs:

T cell receptor excision circles

TCR:

T cell receptor

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Acknowledgements

The authors thank the patients and their families for their collaboration and the expert care by the interdisciplinary pediatric teams. Raz Somech is supported by grants from the Jeffrey Modell Foundation (JMF) and the Israeli Science Foundation (ISF). The authors would like to acknowledge Dr. Abigail Lazar for editing the manuscript.

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Authors and Affiliations

  1. Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, 52621, Tel Hashomer, Israel

    Shirly Frizinsky, Erez Rechavi, Yu Nee Lee, Amos J. Simon, Atar Lev, Raz Somech & Tali Stauber

  2. The Wohl Institute for Translational Medicine and Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel

    Ortal Barel, Yu Nee Lee, Amos J. Simon, Atar Lev, Raz Somech & Tali Stauber

  3. Pediatric Department, Makassed Hospital, Jerusalem, Israel

    Rose H. Najeeb

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

    Shoshana Greenberger, Raz Somech & Tali Stauber

  5. Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel

    Shoshana Greenberger

  6. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

    Chi A. Ma, Guangping Sun, Sarah A. Blackstone & Joshua D. Milner

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  1. Shirly Frizinsky
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Correspondence to Raz Somech.

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Frizinsky, S., Rechavi, E., Barel, O. et al. Novel MALT1 Mutation Linked to Immunodeficiency, Immune Dysregulation, and an Abnormal T Cell Receptor Repertoire. J Clin Immunol 39, 401–413 (2019). https://doi.org/10.1007/s10875-019-00629-0

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  • DOI: https://doi.org/10.1007/s10875-019-00629-0

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