Department of Allergy and Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China.
Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
J Clin Immunol. 2024 Oct 10;45(1):23. doi: 10.1007/s10875-024-01812-8.
FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism.
Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis.
The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RAHLA-DR, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment.
We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.
FAS 基因突变导致自身免疫性淋巴增生综合征（ALPS），该病常以常染色体显性遗传，偶尔以常染色体隐性遗传方式遗传。我们报告了一例新生儿女性患者，存在 FAS 基因的新型复合杂合变异，并揭示了潜在的发病机制。
采用外显子组测序（WES）来鉴定致病性变异。采用多参数流式细胞术分析、phosflow 分析和 FAS 诱导的细胞凋亡实验，来研究变异对 FAS 表达、细胞凋亡和免疫表型的影响。利用 HEK293T 细胞来评估变异对蛋白表达和 FAS 诱导的细胞凋亡的影响。
该患者出生时存在肝脾肿大、贫血和血小板减少。她还经历了 COVID-19、轮状病毒感染、单纯疱疹病毒感染和重症肺炎。双阴性 T 细胞（DNTs）的比例显著升高。鉴定出 FAS 基因的两个新型复合杂合变异：c.310T＞A（p.C104S）和 c.702_704del（p.T235del）。T 细胞的凋亡能力受损，T 细胞表面的 FAS 表达缺失。T235del 变异降低了 FAS 的表达，而 C104S 蛋白滞留在内质网中，无法转运到细胞表面。两种突变均导致 HEK293T 细胞中 FAS 诱导的细胞凋亡功能丧失。DNTs 主要为终末分化的 T（TEMRA）和 CD45RAHLA-DR，高表达 CD85j、PD-1 和 CD57。患者 Th1、Tfh 和自身反应性 B 细胞的比例显著增加。异常的免疫表型经西罗莫司治疗后部分得到改善。
我们鉴定了两个显著影响 FAS 表达或定位的变异，导致胎儿期疾病的早期发病。mTOR 通路的异常与西罗莫司的良好治疗反应相关。
