FAS‐mediated apoptosis impairment in patients with ALPS/ALPS‐like phenotype carrying variants on CASP10 gene

Abstract

Summary Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10‐mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS‐like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS‐ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS‐like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

“…As the insilico analyses were inconclusive, ACMG classification was likely benign. CASP10 c.1228G>A (p.Val410Ile) was found in one patient and co-occurred with another missense CASP10 variant (c.1216A>T) in our cohort, supporting the prediction as a benign variant29,34,35 . ALPS accompanied by possibly pathogenic or benign CASP10…”

“…CASP10 c.1216A>T was considered as a VUS/likely pathogenic variant in our patient cohort as in vitro functional studies proved defective apoptosis in ALPS patients. 29 No literature have previously described the CASP10 c295A>G variant. Biomarker data on ALPS-CASP10 patients are scarcely available, interestingly none of our patients show defective in vitro apoptosis functional assaya and elevated sFASL.…”

“…The clinical symptoms and laboratory biomarkers were evaluated by the ALPS-2010 diagnostic protocol, 3,23 29 , where elevated DNT ratio was only a major, but not a required criterion. The diagnostic protocol was extended: suspected ALPS was defined as the fulfilment of two major and one minor criteria.…”

Thrombotic thrombocytopenic purpura and defective apoptosis due to CASP8/10 mutations: the role of mycophenolate mofetil

“…This variant is generally classified as a high-frequency polymorphism (EXAC DATABASE, http://exac.broadinstitute.org/) even if it was reported with a probably damaging role in most prediction tools; it has also been shown to be associated with an impaired apoptotic capacity. 13,14 The additional weak cleavage inactivation of the PARP protein, along with FAS-L treatment that did not induce any apoptotic death ( Figure 1A), suggests an overall reduction in apoptotic activity in the patient's lymphoid cells.…”

The TNFRSF13C H159Y Variant Is Associated with Severe COVID-19: A Retrospective Study of 500 Patients from Southern Italy

“…The c.475C > T transition results in the H159Y amino acid change within the highly conserved cytoplasmic domain of BAFFR [14]. This variant has already been associated with immune disorders, such as CVID, autoimmune lymphoproliferative syndrome-like disease, multiple sclerosis, Good's syndrome, and Sjogren's syndrome [15][16][17][18][19][20]. Additionally, it has been also associated with an increased risk of chronic lymphocytic leukemia and lymphoma [14,21].…”