Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association

• Published in: Journal of allergy and clinical immunology Vol. 137; no. 3; pp. 879 - 888.e2
• Main Authors: Yee, Christina S., Massaad, Michel J., Bainter, Wayne, Ohsumi, Toshiro K., Föger, Niko, Chan, Andrew C., Akarsu, Nurten A., Aytekin, Caner, Ayvaz, Deniz Çagdas, Tezcan, Ilhan, Sanal, Özden, Geha, Raif S., Chou, Janet
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2016; Elsevier Limited
• Subjects: Actins - chemistry; Actins - metabolism; Adolescent; Allergy and Immunology; Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Degranulation - genetics; Cell Degranulation - immunology; Cell Survival - genetics; Coronin-1A; Cytoskeleton - metabolism; DNA Mutational Analysis; Female; Frameshift Mutation; Homozygote; Humans; immunodeficiency; Immunoglobulins - blood; Immunoglobulins - immunology; Kinases; Lymphocyte Count; Lymphocytes; Lymphopenia; Male; Mice; Microfilament Proteins - chemistry; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Mutation; Pedigree; Phenotype; Protein Multimerization - genetics; Protein Transport; Siblings; Signal Transduction; Skin Diseases - pathology; T-cell lymphopenia; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Varicella-zoster virus; Viral infections; Virus Diseases - diagnosis; Virus Diseases - etiology; Virus Diseases - metabolism; Warts - pathology; CC; CE; WGS; CORO1A; SCID; T-cell lymphopenia; FITC; F-actin; immunodeficiency; MAP; NK; WT; Coronin-1A; Arp; Fluorescein isothiocyanate; Coiled-coil leucine zipper; Severe combined immunodeficiency; Actin-related protein; C-terminal extension; Mitogen-activated protein; Wild-type; Natural killer; Whole-genome sequencing; Filamentous actin
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.08.020

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. 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. We performed immunologic, genetic, and biochemical studies in the patients, family members, and healthy control subjects. 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 CORO1AS401fs 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. CORO1AS401fs 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. 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.