{"title":"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。","authors":"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","doi":"10.1007/s10875-024-01812-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>+</sup>HLA-DR<sup>+</sup>, 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"23"},"PeriodicalIF":7.2000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).\",\"authors\":\"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\",\"doi\":\"10.1007/s10875-024-01812-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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<sup>+</sup>HLA-DR<sup>+</sup>, 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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":15531,\"journal\":{\"name\":\"Journal of Clinical Immunology\",\"volume\":\"45 1\",\"pages\":\"23\"},\"PeriodicalIF\":7.2000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10875-024-01812-8\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10875-024-01812-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).
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.
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.
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