The genetic landscape of the FAS pathway deficiencies

Abstract

Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS mutations. The goal of this review is to describe the genetic bases of the autoimmune lymphoproliferative syndrome and to underline their genetic complexity with the contribution of both germline and somatic events accounting for the variable clinical penetrance of the FAS mutations. Starting from the cohort of patients studied in the French cohort (>165 cases), we also reviewed the literature cases in order to depict a full description of the mutations affecting the FAS-FASLG pathway involved in the outcome of this rare non-malignant and non-infectious pediatric lymphoproliferative disease. We also discussed the variable clinical penetrance associated with mutations affecting the extracellular domain of the protein. Such non-penetrant germline mutations are frequently associated with an additional somatic event impacting the second allele of FAS . Moreover, the uncomplete clinical penetrance associated with mutations affecting the intracellular domain of FAS, in patient lacking additional FAS somatic event, suggested a potential digenic inheritance with a FAS mutation accompanied by a genetic modifier possibly impacting another player of the lymphocytes homeostasis (affecting the survival, activation or apoptosis of the peripheral leukocytes).

We refuse to die – T cells causing havoc

“…They also have a closer look at inherited non-FAS mutations that play a part in ALPS. Finally, they suggest that a second event next to any mutation affecting the FAS induced apoptosis might be involved in ALPS onset [ 4 ].…”

Case Report: Autoimmune Lymphoproliferative Syndrome vs. Chronic Active Epstein-Barr Virus Infection in Children: A Diagnostic Challenge

“…Upon T lymphocyte activation, an expression of Fas ligand (FASL) and its interaction with FAS receptors is triggered, leading subsequently to binding of FAS-associated protein with death domain (FADD). FADD then recruits pro-caspases 8 and 10 to engender the death-inducing signaling complex (DISC) and generates terminal caspase activation leading to cell death (1)(2)(3). This tightly regulated system of controlling lymphocyte stimulation plays a critical role in immune homeostasis thereby preventing an expansion of autoreactive T cells.…”

“…Autoimmune lymphoproliferative syndrome (ALPS) also known as Canale-Smith syndrome is a disorder of the extrinsic first apoptosis signal (FAS)-mediated pathway of lymphocyte apoptosis characterized by marked genetic and clinical heterogeneity ( 1 , 2 ). The hallmarks of the disease are childhood-onset chronic non-malignant, non-infectious lymphoproliferation manifesting as lymphadenopathy and/or splenomegaly, autoimmune cytopenia, and polyclonal IgG hypergammaglobulinemia.…”

“…This tightly regulated system of controlling lymphocyte stimulation plays a critical role in immune homeostasis thereby preventing an expansion of autoreactive T cells. Abnormal FAS-mediated activation-induced apoptosis pathway is caused by germline or somatic mutations in FAS which is the main genetic defect in the majority of ALPS patients ( 2 , 4 ), FASLG, CASP8 , and CASP10 genes, encoding crucial elements of AICD, Fas cell surface death receptor protein, FAS ligand protein, and caspases 8 and 10, respectively ( 5 ). While widely considered to be a primary immune deficiency presenting in early childhood, an ever-growing understanding of the immunogenetic background of ALPS has led to increasingly recognized adult-onset and ALPS-like disorders with mutations in NRAS and KRAS genes as well ( 5 ).…”

Scaling the tips of the ALPS

“…In the first review article, Dr. Magerus and her colleagues analyze mutations affecting the FAS pathway associated with ALPS diagnosed in 130 patients of a French cohort, in addition to the mutations described in the literature [ 3 ]. In the first part of this review, the Fas/Faslg autosomal recessive mutations identified in mice are compared to the FAS/FASLG mutations in humans.…”