Table_2_Novel TMEM173 Mutation and the Role of Disease Modifying Alleles.pdf

Upon binding to pathogen or self-derived cytosolic nucleic acids cyclic GMP-AMP synthase (cGAS) triggers the production of cGAMP that further activates transmembrane protein STING. Upon activation STING translocates from ER via Golgi to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms underlying the variable phenotype-genotype correlation are presently unclear. Here, we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and features of STING-associated vasculopathy with onset in infancy (SAVI), such as livedo reticularis, skin vasculitis, nasal septum perforation, facial erythema, and bacterial infections. Polymorphism in TMEM173 and IFIH1 showed variable penetrance in the affected family, implying contribution to varying phenotype spectrum. The G207E mutation constitutively activates inflammation-related pathways in vitro, and causes aberrant interferon signature and inflammasome activation in patient PBMCs. Treatment with Janus kinase 1 and 2 (JAK1/2) inhibitor baricitinib was beneficiary for a vasculitic ulcer, induced hair regrowth and improved overall well-being in one patient. Protein-protein interactions propose impaired cellular trafficking of G207E mutant. These findings reveal the molecular landscape of STING and propose common polymorphisms in TMEM173 and IFIH1 as likely modifiers of the phenotype.

当结合病原体或自身来源的胞质核酸后，环GMP-AMP合酶（cGAS）会触发环GMP-AMP（cGAMP）的产生，后者进一步激活跨膜蛋白STING。激活后的STING会从内质网（ER）经高尔基体转运至囊泡。单基因STING功能获得性突变会导致早发性I型干扰素病，其疾病表现谱从致死性血管病延伸至轻度冻疮样狼疮。目前，这种可变的表型-基因型关联背后的分子机制尚不明确。本研究报道了一种新型功能获得性G207E STING突变，该突变可引发独特的表型，包括脱发、光敏感、甲状腺功能异常，以及婴儿起病的STING相关血管病（SAVI）相关特征，如网状青斑、皮肤血管炎、鼻中隔穿孔、面部红斑与细菌感染。TMEM173与IFIH1的多态性在受累家系中表现出可变的外显率，提示其可能参与了表型谱的变异。体外实验显示，G207E突变会持续性激活炎症相关通路，并在患者外周血单个核细胞（PBMCs）中引发异常的干扰素特征与炎症小体激活。使用贾纳斯激酶1/2（JAK1/2）抑制剂巴瑞替尼进行治疗，可改善一名患者的血管炎性溃疡、促进毛发再生，并提升其整体健康状况。蛋白质相互作用实验提示，G207E突变体的细胞运输过程存在缺陷。本研究揭示了STING相关的分子特征谱，并提出TMEM173与IFIH1的常见多态性可能作为表型的修饰因子。