LRBA functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis.

Abstract

BACKGROUND Biallelic loss-of-function (LOF) mutations in LRBA (lipopolysaccharide-responsive and beige-like anchor) lead to a severe syndrome of early-onset immune dysregulation called LRBA deficiency. Monoallelic CTLA4 mutations lead to a similar phenotype. In both conditions, Treg CTLA-4 levels are significantly decreased. In previously reported cases of symptomatic disease associated with LRBA pathogenic variants, patients usually have severely decreased or absent LRBA protein levels. OBJECTIVE We describe here five patients with biallelic missense variants in the LRBA gene presenting predominantly with Evans syndrome or colitis. METHODS LRBA and CTLA-4 levels were investigated in LRBA missense, "classic" LRBA, and CTLA-4 insufficiency samples. RESULTS Surprisingly, all five LRBA missense patients have normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in CTLA-4 insufficiency patients at resting state. Lower levels of surface CTLA-4 are seen upon cell activation, indicating that these LRBA variants lead to reduced CTLA-4 cell surface expression. Several of the missense variants are shared between unrelated patients in the cohort suggesting a mutational hotspot or founder effect for those with shared ancestry. CONCLUSION Herein, we describe novel LRBA deficiency variants resulting in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.