Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS).
FAS
Apoptosis
Autoimmune Lymphoproliferation Syndrome
Compound heterozygous mutations
Double-negative T Cells
Immunophenotyping
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
10 Oct 2024
10 Oct 2024
Historique:
received:
20
05
2024
accepted:
21
09
2024
medline:
10
10
2024
pubmed:
10
10
2024
entrez:
9
10
2024
Statut:
epublish
Résumé
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 CD45RA 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.
Identifiants
pubmed: 39384643
doi: 10.1007/s10875-024-01812-8
pii: 10.1007/s10875-024-01812-8
doi:
Substances chimiques
fas Receptor
0
FAS protein, human
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Subventions
Organisme : "Sailing Program" of Shanghai Science and Technology Committee
ID : 23YF1403400
Organisme : Shanghai Municipal Technology Standards Project
ID : 23DZ2202600
Organisme : Shanghai Municipal Science and Technology Major Project
ID : 2023SHZDZX02, 2017SHZDZX01
Organisme : Shanghai Municipal Science and Technology Major Project
ID : ZD2021CY001
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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