Inflamm Bowel Dis 2015 Jan;21(1):40-7
*CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; †Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey; ‡Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; §Department of Pediatric Gastroenterology, Akdeniz University, Antalya, Turkey; ‖Konya Training and Research Hospital, Konya, Turkey; ¶Department of Pathology, Ankara University, Ankara, Turkey; and **Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Background: Inflammatory bowel diseases (IBDs) denote a heterogeneous group of disorders associated with an imbalance of gut microbiome and the immune system. Importance of the immune system in the gut is endorsed by the presence of IBD-like symptoms in several primary immunodeficiencies. A fraction of early-onset IBDs presenting with more severe disease course and incomplete response to conventional treatment is assumed to be inherited in a Mendelian fashion, as exemplified by the recent discovery of interleukin (IL)-10 (receptor) deficiency.
Methods: We analyzed a patient born to consanguineous parents suffering from severe intestinal manifestations since 6 months of age and later diagnosed as IBD. Eventually, she developed autoimmune manifestations including thyroiditis and type I diabetes at the age of 6 and 9 years, respectively. Combined single-nucleotide polymorphism array-based homozygosity mapping and exome sequencing was performed to identify the underlying genetic defect. Protein structural predictions were calculated using I-TASSER. Immunoblot was performed to assess protein expression. Flow cytometric analysis was applied to investigate B-cell subpopulations.
Results: We identified a homozygous missense mutation (p.Ile2824Pro) in lipopolysaccharide-responsive and beige-like anchor (LRBA) affecting the C-terminal WD40 domain of the protein. In contrast to previously published LRBA-deficient patients, the mutant protein was expressed at similar levels to healthy controls. Immunophenotyping of the index patient revealed normal B-cell subpopulations except increased CD21 B cells.
Conclusions: We describe a patient with a novel missense mutation in LRBA who presented with IBD-like symptoms at early age, illustrating that LRBA deficiency should be considered in the differential diagnosis for IBD(-like) disease even in the absence of overt immunodeficiency.