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. 2025 Aug;156(2):270-278.
doi: 10.1016/j.jaci.2025.04.003. Epub 2025 Apr 10.

Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis

Samuel C C Chiang  1 , Li Yang  2 , Erika Owsley  2 , Ammar Husami  3 , Nagako Akeno  2 , Cristina Cobb  2 , Nicholas L Hartog  4 , Araceli Elizalde  5 , Christine M Seroogy  6 , Geraldine Blanchard-Rohner  7 , Xiao P Peng  8 , Rae Brager  9 , David Buchbinder  10 , Eleanor Cook  11 , Lindsay Phillips  12 , Snezana Plecas Maricic  12 , Tatiana Kalashnikova  13 , Beata Derfalvi  14 , Victoria R Dimitriades  15 , Luis E Murguía-Favela  13 , Maria J Gutierrez  16 , Anitha Shrikhande  17 , MacGregor Steele  13 , Jo L Wilson  6 , Nicola A M Wright  13 , Rebecca Marsh  11 , Jack Bleesing  11 , Michael B Jordan  11 , Ashish K Marwaha  18
Affiliations

Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis

Samuel C C Chiang et al. J Allergy Clin Immunol. 2025 Aug.

Abstract

Background: Biallelic loss-of-function mutations in the lipopolysaccharide-responsive and beige-like anchor (LRBA) gene lead to a severe syndrome of early-onset immune dysregulation called LRBA deficiency. Monoallelic CTLA4 mutations lead to a similar phenotype. In both conditions, cytotoxic T lymphocyte-associated protein 4 (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 5 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 in CTLA-4 insufficiency samples.

Results: Surprisingly, all 5 LRBA missense patients had normal expression of LRBA protein. However, CTLA-4 intracellular expression was reduced to similar levels as those seen in patients with CTLA-4 insufficiency at resting state. Lower levels of surface CTLA-4 are seen on 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 hot spot or founder effect for those with shared ancestry.

Conclusion: Novel LRBA deficiency variants result in quantitative or qualitative LRBA defects, leading to reduced intracellular resting levels and induced surface levels of CTLA-4.

Keywords: CTLA-4; Evans syndrome; Inborn errors of immunity; LRBA; T regulatory cells; colitis; functional cell testing; functional deficiency.

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Conflict of interest statement

Disclosure statement Disclosure of potential conflict of interest: A. Elizalde reports acting as speaker for Blueprint Medicines. N. L. Hartog reports acting as speaker and consultant for Amgen; speaker, consultant, and scientific advisory board member for Pharming Healthcare; and speaker for X4 Pharma and Takeda. L. E. Murguía-Favela is a member of the data monitoring committee for Encoded Therapeutics. X. P. Peng reports acting as speaker for Pharming. N. A. M. Wright is supported by the Barb Ibbotson Chair in Pediatric Hematology, Alberta Children’s Hospital Foundation. The rest of the authors declare that they have no relevant conflicts of interest.

Supplementary concepts