St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
Primary Immunodeficiencies Group, University of Antioquia, Medellin, Colombia.
J Exp Med. 2022 Oct 3;219(10). doi: 10.1084/jem.20220094. Epub 2022 Sep 12.
Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
纯合子携带罕见 TYK2 失活（LOE）等位基因的人类细胞对 IFN-α/β（患者的潜在病毒疾病）和 IL-12 和 IL-23（潜在的分枝杆菌疾病）的细胞反应受损，但未完全丧失。纯合子携带常见的 P1104A TYK2 等位基因的细胞对 IL-23（潜在的孤立分枝杆菌疾病）的反应选择性受损。我们报告了来自五个家族的六名患者中的三种新形式的 TYK2 缺乏症，这些患者均为罕见 TYK2 等位基因（R864C、G996R、G634E 或 G1010D）或 P1104A 和罕见等位基因（A928V）的复合杂合子纯合子。所有这些错义等位基因均编码可检测的蛋白质。R864C 和 G1010D 等位基因在信号通路中分别为功能缺失（LOF）和功能减弱（Hypomorphic）。相比之下，功能减弱的 G996R、G634E 和 A928V 突变选择性地损害了对 IL-23 的反应，类似于 P1104A。IL-23 依赖性 IFN-γ 诱导受损是 TYK2 完全缺乏症或缺乏 TYK2 表达、信号通路中部分 TYK2 缺乏症、或罕见或常见的特定于 IL-23 信号的部分 TYK2 缺乏症的唯一分枝杆菌病发病机制。
