Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) functional deficiency caused by biallelic LRBA missense variants characterized by Evans syndrome or colitis - 06/05/25

Doi : 10.1016/j.jaci.2025.04.003

Samuel C.C. Chiang, PhD ^a,^b,^⁎ , Li Yang, MD, PhD ^a, Erika Owsley, BS ^a, Ammar Husami, BS ^c, Nagako Akeno, PhD ^a, Cristina Cobb, BS ^a, Nicholas L. Hartog, MD ^d, Araceli Elizalde, MD ^e, Christine M. Seroogy, MD ^f, Geraldine Blanchard-Rohner, MD, PhD ^g, Xiao P. Peng, MD, PhD ^h, Rae Brager, MD ⁱ, David Buchbinder, MD ^j, Eleanor Cook, MD ^a,^b, Lindsay Phillips, PhD ^k, Snezana Maricic, MD ^k, Tatiana Kalashnikova, MD, PhD ^l, Beata Derfalvi, MD, PhD ^m, Victoria R. Dimitriades, MD ⁿ, Luis E. Murguía-Favela, MD ^l, Maria J. Gutierrez, MD, MHS, MBA ^o, Anitha Shrikhande, MD ^p, MacGregor Steele, MD ^l, Jo L. Wilson, MD ^f, Nicola A.M. Wright, MD ^l, Rebecca Marsh, MD ^a,^b, Jack Bleesing, MD, PhD ^a,^b, Michael B. Jordan, MD ^a,^b, Ashish K. Marwaha, BMBch, PhD ^k,^⁎
^a Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
^b Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
^c Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
^d Allergy and Immunology, Corwell Health, Helen Devos Children’s Hospital, College of Human Medicine, Michigan State University, Grand Rapids, Mich
^e Allergy and Asthma, Texas Health, San Antonio, Tex
^f Division of Allergy, Immunology & Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis
^g Unit of Immunology, Vaccinology and Rheumatology, Division of General Pediatrics, Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
^h Division of Genetic Medicine, Department of Pediatrics, Montefiore Medical Center, Bronx, NY
ⁱ Division of Rheumatology, Immunology and Allergy, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
^j Division of Hematology, Children’s Hospital of Orange County, Orange, Calif
^k Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Ontario, Canada
^l Section of Hematology/Immunology, Alberta Children’s Hospital, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
^m Division of Immunology, Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada
ⁿ Division of Pediatric Allergy, Immunology & Rheumatology, UC Davis Health, Sacramento, Calif
^o Division of Pediatric Allergy, Immunology and Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Md
^p Department of Medicine and Pediatrics, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY

^∗Corresponding authors: Ashish K. Marwaha BMBch, PhD, Department of Medical Genetics, Alberta Children’s Hospital, 28 Oki Dr NW, Calgary, AB, Canada, T3B 6A8.Department of Medical GeneticsAlberta Children’s Hospital28 Oki Dr NWCalgaryABT3B 6A8Canada^∗∗Samuel Samuel C. C. Chiang, PhD, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 7015, Cincinnati, OH 45229.Cincinnati Children’s Hospital Medical Center3333 Burnet AveMLC 7015CincinnatiOH45229

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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.

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Key words : Inborn errors of immunity, CTLA-4, LRBA, functional deficiency, Evans syndrome, colitis, functional cell testing, T regulatory cells

Abbreviations used : CTLA-4, ITP, IVIG, LRBA, MdFI, NK, TCR, Treg