The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.
The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.
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携带隐性外周T细胞缺陷（Ptcd）基因座的小鼠胸腺出口阻滞，但其机制尚不清楚。在这里，我们发现Ptcd T细胞具有内在的迁移缺陷，淋巴组织运输受损和不规则形状的突起。Ptcd基因座的特征显示，在肌动蛋白调节蛋白冠蛋白1a （Coro1a）中存在E26K点突变，该突变增强了其对肌动蛋白调节蛋白Arp2/3的抑制作用，并导致其在迁移T细胞的前沿错误定位。在对T细胞淋巴细胞减少小鼠进行n -乙基-n -亚硝基脲（ENU）诱变筛选时，发现了另一个Coro1a突变体，这促使我们对一个T细胞缺陷、B细胞和NK细胞充足（T - B+NK+）严重联合免疫缺陷（SCID）患者进行评估，我们发现该患者的两个Coro1a等位基因都发生了突变。这些发现确立了冠状蛋白1a在T细胞输出中的作用，确定了冠状蛋白参与Arp2/3调控的一个表面，揭示了肌动蛋白调控在人和小鼠SCID中是一个有缺陷的生物学过程。
Mice carrying the recessive peripheral T cell deficiency (Ptcd) locus have a block in thymic egress but the mechanism responsible is undefined. Here we found that Ptcd T cells have an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus revealed an E26K point mutation within the actin regulator coronin-1A (Coro1a) that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. Discovery of another Coro1a mutant during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen for T cell lymphopenic mice prompted us to evaluate a T cell-deficient, B cell- and NK cell-sufficient (T−B+NK+) severe combined immunodeficiency (SCID) patient, whom we found had mutations in both CORO1A alleles. These findings establish a role for coronin-1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation, and reveal actin regulation as a biological process defective in human and mouse SCID.