Mutations in several proteins functioning as endolysosomal components cause monogenic autoimmune diseases, of which pathogenesis is linked to increased endoplasmic reticulum stress, inefficient autophagy, and defective recycling of immune receptors. We report here a heterozygous TOM1 p.G307D missense mutation, detected by whole-exome sequencing, in two related patients presenting with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. The index patient suffered from recurrent respiratory tract infections and oligoarthritis since early teens, and later developed persistent low-copy EBV-viremia, as well as an antibody deficiency. Her infant son developed hypogammaglobulinemia, autoimmune enteropathy, interstitial lung disease, profound growth failure, and treatment-resistant psoriasis vulgaris. Consistent with previous knowledge on TOM1 protein function, we detected impaired autophagy and enhanced susceptibility to apoptosis in patient-derived cells. In addition, we noted diminished STAT and ERK1/2 signaling in patient fibroblasts, as well as poor IFN-γ and IL-17 secretion in T cells. The mutant TOM1 failed to interact with TOLLIP, a protein required for IL-1 recycling, PAMP signaling and autophagosome maturation, further strengthening the link between the candidate mutation and patient pathophysiology. In sum, we report here an identification of a novel gene, TOM1, associating with early-onset autoimmunity, antibody deficiency, and features of combined immunodeficiency. Other patient cases from unrelated families are needed to firmly establish a causal relationship between the genotype and the phenotype.

充当溶酶体成分的几种蛋白质中的突变会导致单基因自身免疫性疾病，其发病机理与内质网应激增加，自噬效率低下以及免疫受体循环不良有关。我们在这里报告了杂合的TOM1通过全外显子组测序检测到的p.G307D错义突变在两名相关患者中表现出早发性自身免疫，抗体缺乏和合并免疫缺陷的特征。索引患者自十几岁起就患有反复呼吸道感染和寡关节炎，后来发展为持续的低拷贝EBV病毒血症以及抗体缺乏症。她的小儿子发展成低血球蛋白血症，自身免疫性肠病，间质性肺病，严重的生长衰竭和寻常型牛皮癣。与以前对TOM1蛋白功能的认识一致，我们检测到自噬功能受损，并且患者来源的细胞对凋亡的敏感性增强。此外，我们注意到患者成纤维细胞中的STAT和ERK1 / 2信号减弱，以及T细胞中的IFN-γ和IL-17分泌不良。突变体TOM1无法与ILLL回收，PAMP信号传导和自噬小体成熟所需的蛋白质TOLLIP相互作用，从而进一步加强了候选突变与患者病理生理之间的联系。总而言之，我们在这里报告一种新基因的鉴定，TOM1，与早期发作的自身免疫，抗体缺乏和合并的免疫缺陷的特征有关。需要从不相关的家庭获得其他患者病例，以牢固地建立基因型和表型之间的因果关系。