Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.

Clinical, immunological, and genetic features in 780 patients with autoimmune lymphoproliferative syndrome (ALPS) and ALPS‐like diseases: A systematic review

“…Somatic pathogenic variants have not been reported in other ALPS-related genes up to now. 14,33 Similar to previous reports, male-to-female ratio in ALPS-FAS with heterozygous germinal mutation, with malignancy, and also with the somatic mutation was high. [34][35][36] The majority of FAS mutations in the intracellular domain are missense with dominantnegative effects that have a great impact on protein expression 37,38 despite the mutations of the extracellular region that have haploinsufficiency effect.…”

“…40 Similarly, clinical penetrance, in contrast to cellular penetrance, is lower in patients with extracellular domain mutations in comparison with patients with a defect in the intracellular domain. 33 Altogether, the location and type of pathogenic variants, modifier genes, additional mutation, or exposure to environmental factors may explain the variable penetrance. 5,33,40,41 The main focus in the treatment of ALPS patients is directed toward the management of autoimmunity and lymphoproliferation, as well as the prevention of lymphoma.…”

“…33 Altogether, the location and type of pathogenic variants, modifier genes, additional mutation, or exposure to environmental factors may explain the variable penetrance. 5,33,40,41 The main focus in the treatment of ALPS patients is directed toward the management of autoimmunity and lymphoproliferation, as well as the prevention of lymphoma. In patients with severe lymphoproliferative manifestations or with concomitant autoimmunity, immunosuppressive agents were suggested, and among others, targeted biologics were associated with fewer complications.…”

Mutations primarily alter the inclusion of alternatively spliced exons

“…In these DMS experiments, the effects of hundreds or thousands of mutations in or around an exon are quantified in parallel by selection and sequencing. Exons subjected to DMS include FAS exon 6 ( Julien et al, 2016 ), whose inclusion is altered in autoimmune lymphoproliferative syndrome ( Ben-Mustapha et al, 2018 ); RON exon 11 ( Braun et al, 2018 ), whose skipping can promote oncogenesis ( Collesi et al, 1996 ); and WT1 exon 5 ( Ke et al, 2018 ), whose inclusion in leukemic cells confers resistance to chemotherapy drugs ( Yang et al, 2007 ). These studies revealed that 60–70% of all single-nucleotide substitutions and mutations in over 90% of exon positions alter exon inclusion ( Braun et al, 2018 ; Julien et al, 2016 ; Ke et al, 2018 ).…”

Targeted therapy for intervertebral disc degeneration: inhibiting apoptosis is a promising treatment strategy

“…The human IVD is an immune-privileged organ with functional FasL expression. Studies have shown that the Fas-FasL apoptosis mechanism maintains immune privilege by interacting with invasive immune cells 36 , 54 .…”