FASLG – Autoimmune lymphoproliferative syndrome type 1

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic nonmalignant lymphoproliferation, expansion of double-negative T cells, hypergammaglobulinemia, and autoimmune cytopenias. ALPS is most commonly due to heterozygous FAS mutations, but rare cases arise from biallelic defects in FASLG ([PMID:22857792]). The inheritance in ALPS-FASLG is autosomal recessive with complete loss of Fas ligand function.

Two unrelated patients have been described with homozygous loss-of-function FASLG variants and classic ALPS features. The first case carries a homozygous c.343C>T (p.Arg115Ter) variant leading to undetectable FasL expression; both consanguineous parents are heterozygous carriers with normal phenotype ([PMID:22857792]). The second patient harbors a novel homozygous missense variant c.605G>C (p.Cys202Ser) and presented with severe lymphoproliferation; his deceased brother had a similar clinical course, confirming familial segregation ([PMID:26334989]).

No pathogenic FASLG variants were detected in a cohort of 25 probable ALPS patients lacking FAS mutations, suggesting FASLG defects account for a minority of ALPS cases ([PMID:26690594]). This underlines the rarity of ALPS-FASLG and the need for targeted sequencing in unexplained AR lymphoproliferative phenotypes.

Functional studies demonstrate defective activation-induced cell death (AICD) in patient T-cell blasts and EBV-transformed B cells with FASLG mutations, with impaired cytotoxicity assays recapitulating the human phenotype ([PMID:26334989]). In gld mice, the non-functional FasL (Phe→Leu) maintains normal expression but fails to induce apoptosis, leading to lymphadenopathy and autoimmunity ([PMID:7495745]).

Collectively, these data support a limited but consistent association between biallelic FASLG loss-of-function and AR ALPS. Screening for FASLG should be considered in ALPS patients without FAS defects, particularly in consanguineous families. Key Take-home: Biallelic FASLG null or damaging variants cause severe AR ALPS and robust functional assays facilitate diagnosis.

References

• The Journal of allergy and clinical immunology • 2013 • Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. PMID:22857792
• Pediatric research • 2015 • Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation. PMID:26334989
• The Turkish journal of pediatrics • 2015 • Polymorphisms in FAS and CASP8 genes may contribute to the development of ALPS phenotype: a study in 25 patients with probable ALPS. PMID:26690594
• International immunology • 1995 • Characterization of the non-functional Fas ligand of gld mice. PMID:7495745

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