title: Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype.
abstract: 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.
authors.affiliation: *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.
authors.forename: Nina Kathrin
authors.initials: NK
authors.lastname: Serwas
authors.forename: Aydan
authors.initials: A
authors.lastname: Kansu
authors.forename: Elisangela
authors.initials: E
authors.lastname: Santos-Valente
authors.forename: Zarife
authors.initials: Z
authors.lastname: Kuloğlu
authors.forename: Arzu
authors.initials: A
authors.lastname: Demir
authors.forename: Aytaç
authors.initials: A
authors.lastname: Yaman
authors.forename: Laura Yaneth
authors.initials: LY
authors.lastname: Gamez Diaz
authors.forename: Reha
authors.initials: R
authors.lastname: Artan
authors.forename: Ersin
authors.initials: E
authors.lastname: Sayar
authors.forename: Arzu
authors.initials: A
authors.lastname: Ensari
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018389:Codon, Nonsense / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D006720:Homozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C428703:LRBA protein, human