Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).

IF 7.2 2区医学 Q1 IMMUNOLOGY

Journal of Clinical Immunology Pub Date : 2024-10-10 DOI:10.1007/s10875-024-01812-8

Qi Wu, Bijun Sun, Jia Hou, Xiaoying Hui, Chenghao Wang, Wenjie Wang, Wenjing Ying, Luyao Liu, Li Zhu, Ying Wang, Qifan Li, Meiping Yu, Weitao Zhou, Yao Chen, Bingbing Wu, Jinqiao Sun, Qinhua Zhou, Feng Qian, Xiaochuan Wang

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引用次数: 0

Abstract

Objective: 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.

Methods: 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.

Results: 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 CD45RA⁺HLA-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.

Conclusions: 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.

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FAS 基因中的新型复合杂合子变异导致自身免疫淋巴细胞增生综合征 (ALPS) 在胎儿期发病。

目的：FAS基因缺陷会导致自身免疫性淋巴组织增生综合征（ALPS），该综合征通常为常染色体显性遗传，很少为常染色体隐性遗传。我们报告了一例患有 FAS 新型复合杂合子变异的新生女婴，并揭示了其潜在机制：方法：采用全外显子组测序（WES）鉴定致病变异。方法：采用全外显子组测序技术（WES）鉴定致病变异体，并使用多参数流式细胞术分析、phosflow分析和FAS诱导细胞凋亡测定来探讨变异体对FAS表达、细胞凋亡和免疫表型的影响。用HEK293T细胞评估变体对蛋白质表达和FAS诱导的细胞凋亡的影响：患者出生时患有肝脾肿大、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（DNT）比例明显升高。发现了新的 FAS 复合杂合变体 c.310T > A (p.C104S) 和 c.702_704del (p.T235del)。T细胞的凋亡能力有缺陷，T细胞表面的FAS表达也有缺陷。T235del 变异降低了 FAS 的表达，而 C104S 蛋白则停留在内质网（ER）中，不能转运到细胞表面。这两种突变都导致了 FAS 在 HEK293T 细胞中诱导细胞凋亡的功能缺失。DNTs 主要是终末分化 T（TEMRA）和 CD45RA+HLA-DR+ 细胞，CD85j、PD-1 和 CD57 高表达。患者体内Th1、Tfh和自反应性B细胞的比例明显增加。西罗莫司治疗可部分缓解异常免疫分型：结论：我们发现了两种严重影响 FAS 表达或定位的变异，它们会导致胎儿早期发病。mTOR通路的异常与对西罗莫司的良好反应有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Clinical Immunology 医学-免疫学

CiteScore

12.20

自引率

9.90%

发文量

218

审稿时长

2 months

期刊介绍： The Journal of Clinical Immunology publishes impactful papers in the realm of human immunology, delving into the diagnosis, pathogenesis, prognosis, or treatment of human diseases. The journal places particular emphasis on primary immunodeficiencies and related diseases, encompassing inborn errors of immunity in a broad sense, their underlying genotypes, and diverse phenotypes. These phenotypes include infection, malignancy, allergy, auto-inflammation, and autoimmunity. We welcome a broad spectrum of studies in this domain, spanning genetic discovery, clinical description, immunologic assessment, diagnostic approaches, prognosis evaluation, and treatment interventions. Case reports are considered if they are genuinely original and accompanied by a concise review of the relevant medical literature, illustrating how the novel case study advances the field. The instructions to authors provide detailed guidance on the four categories of papers accepted by the journal.