Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.
Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.
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DOI：
10.1016/j.jaci.2015.08.020
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Chou J
中科院分区：
文献类型：
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作者：
Yee CS;Massaad MJ;Bainter W;Ohsumi TK;Föger N;Chan AC;Akarsu NA;Aytekin C;Ayvaz DÇ;Tezcan I;Sanal Ö;Geha RS;Chou J
冠状蛋白1a （CORO1A）是肌动蛋白动力学的调节因子，对T细胞稳态很重要。CORO1A缺陷导致T - B+NK+严重联合免疫缺陷或T细胞淋巴细胞减少伴严重病毒感染。然而，由于所有已知的人类CORO1A突变都取消了蛋白的表达，因此该蛋白的功能域在宿主免疫中的作用尚不清楚。确定原发性免疫缺陷的原因在两个年轻的成年兄弟姐妹与播散性水痘，皮肤疣，和CD4+ T细胞淋巴减少的历史。我们对患者、家庭成员和健康对照进行了免疫学、遗传学和生化研究。两例患者均有CD4+ T细胞淋巴减少和淋巴细胞向丝裂原增殖减少。IgG、IgM、IgA及特异性抗体反应正常。全基因组测序鉴定出CORO1A的纯合子移码突变，通过将61 a.a.替换为新的91 a.a.序列，破坏了最后两个c端结构域。CORO1AS401fs突变体在患者淋巴细胞中的表达水平与正常淋巴细胞中野生型CORO1A的表达水平相当，但不能寡聚，并且细胞骨架关联受损。CORO1AS401fs与T细胞中f -肌动蛋白积累增加、胸腺输出严重缺陷和T细胞存活受损有关，但钙通量和细胞毒性正常，这表明CORO1A低聚体化和亚细胞定位在T细胞稳态中的重要性。我们描述了CORO1A的截断突变，该突变允许蛋白质表达并存活到年轻的成年期。我们的研究证明了完整的CORO1A c端结构域在胸腺输出和T细胞存活以及对病毒病原体的防御中的重要性。
Coronin-1A (CORO1A) is a regulator of actin dynamics important for T cell homeostasis. CORO1A deficiency causes T−B+NK+ severe combined immunodeficiency or T cell lymphopenia with severe viral infections. However, since all known human mutations in CORO1A abrogate protein expression, the role of the protein’s functional domains in host immunity is unknown. To identify the cause of the primary immunodeficiency in two 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 controls. 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 two C-terminal domains by replacing 61 a.a. with a novel 91 a.a. sequence. The CORO1AS401fs mutant was expressed in the patients’ lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes, but failed to oligomerize and had impaired cytoskeletal association. CORO1AS401fs was associated with increased F-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 oliogomerization 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 the defense against viral pathogens.