A Novel Pathogenic Variant in CARMIL2 (RLTPR) Causing CARMIL2 Deficiency and EBV-Associated Smooth Muscle Tumors
CARMIL2 deficiency is a rare combined immunodeficiency (CID) characterized by defective CD28-mediated T cell co-stimulation, altered cytoskeletal dynamics, and susceptibility to Epstein Barr Virus smooth muscle tumors (EBV-SMTs). Case reports associated with EBV-SMTs are limited. We describe herein a novel homozygous CARMIL2 variant (c.1364_1393del) in two Saudi Arabian male siblings born to consanguineous parents who developed EBV-SMTs. CARMIL2 protein expression was significantly reduced in CD4+ T cells and CD8+ T cells. T cell proliferation on stimulation with soluble (s) anti-CD3 or (s) anti-CD3 plus anti-CD28 antibodies was close to absent in the proband, confirming altered CD28-mediated co-signaling. CD28 expression was substantially reduced in the proband's T cells, and was diminished to a lesser degree in the T cells of the younger sibling, who has a milder clinical phenotype. Defects in both T and B cell compartments were observed, including absent central memory CD8+ T cells, and decreased frequencies of total and class-switched memory B cells. FOXP3+ regulatory T cells (Treg) were also quantitatively decreased, and furthermore CD25 expression within the Treg subset was substantially reduced. These data confirm the pathogenicity of this novel loss-of-function (LOF) variant in CARMIL2 and expand the genotypic and phenotypic spectrum of CIDs associated with EBV-SMTs.
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REFERENCES
- https://doi.org//10.3389/fimmu.2018.00203
- https://doi.org//10.1007/s10875-019-00628-1
- https://doi.org//10.1007/s10875-019-00631-6
- https://doi.org//10.1016/j.clim.2019.06.004
- https://doi.org//10.1093/ibd/izz103
- https://doi.org//10.2340/00015555-3370
- https://doi.org//10.1038/ncomms14209
- https://doi.org//10.1002/mgg3.237
- https://doi.org//10.1084/jem.20160576
- https://doi.org//10.3389/fimmu.2018.00368
- https://doi.org//10.1016/j.anndiagpath.2019.151413
- https://doi.org//10.1091/mbc.e17-01-0019
- https://doi.org//10.1002/0471142905.hg0720s76
- https://doi.org//10.1093/hmg/ddu733
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AUTHORS (10)
CATEGORIES
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity