University of Paris Cité, Paris, France; Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France; Imagine Institute, INSERM UMR 1163, Paris, France.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Allergy Clin Immunol. 2024 Jan;153(1):203-215. doi: 10.1016/j.jaci.2023.09.028. Epub 2023 Oct 2.
The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated.
We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent.
We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4 or DN T cells.
We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations.
The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS.
自身免疫性淋巴增生综合征（ALPS）是一种非传染性和非恶性的淋巴增生性疾病，常与由于 Fas 信号缺陷导致的自身免疫性细胞减少症有关。我们之前描述了与体细胞事件相关的单等位基因 Fas（TNFRSF6）部分不足突变，例如 Fas 的第二个等位基因的杂合性丢失，这是 ALPS-FAS 的一个原因。这些体细胞事件是通过对双阴性（DN）T 细胞中的 Fas 进行测序鉴定的，DN-T 细胞是 ALPS 中特有的 T 细胞亚群，体细胞事件在该亚群中积累。
我们试图确定是否会影响 Fas 相关死亡结构域（FADD）基因的体细胞事件与 4 名携带 Fas 蛋白单等位基因突变的无关患者的疾病发病有关，这些突变是从健康父母那里遗传的。
我们对 FADD 进行测序，并使用来自分选的 CD4 或 DN-T 细胞的 DNA 进行基于阵列的比较基因组杂交。
我们在所有 4 名患者的 DN-T 细胞中发现了 FADD 的纯合突变，这些突变是由于单亲二倍体引起的。由单等位基因突变引起的 FADD 缺陷与体细胞杂合性丢失有关，是 ALPS-FAS 的表型，没有报道的更复杂的症状，这些症状见于 Fas 基因双等位基因突变的患者。
影响 FADD 基因的种系和体细胞事件的关联是 ALPS 的一个新的遗传原因。
