期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 137, 期 3, 页码 879-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.08.020
关键词
Coronin-1A; immunodeficiency; T-cell lymphopenia
资金
- National Institutes of Health [P01AI-076210, AI-094017, T32 AI-007512-26]
- Dubai-Harvard Foundation for Medical Research
- Perkins Fund
- Jeffrey Modell Foundation
- Hacettepe Scientific Research Projects Unit (BAP) [010-01-101-010]
Background: Coronin-1A (CORO1A) is a regulator of actin dynamics important for T-cell homeostasis. CORO1A deficiency causes T-B+ natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections. However, because all known human mutations in CORO1A abrogate protein expression, the role of the protein's functional domains in host immunity is unknown. Objective: We sought to identify the cause of the primary immunodeficiency in 2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia. Methods: We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. Results: Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens. IgG, IgM, IgA, and specific antibody responses were normal. Whole-genome sequencing identified a homozygous frameshift mutation in CORO1A disrupting the last 2 C-terminal domains by replacing 61 amino acids with a novel 91-amino-acid sequence. The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association. CORO1A(S401fs) was associated with increased filamentous actin accumulation in T cells, severely defective thymic output, and impaired T-cell survival but normal calcium flux and cytotoxicity, demonstrating the importance of CORO1A oligomerization and subcellular localization in T-cell homeostasis. Conclusions: We describe a truncating mutation in CORO1A that permits protein expression and survival into young adulthood. Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens.
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