LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency Abdullah Alangari, MD,

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LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency Abdullah Alangari, MD, Abdulrahman Alsultan, MD, Nouran Adly, BSc, Michel J. Massaad, PhD, Iram Shakir Kiani, MD, Abdulrahman Aljebreen, MD, Emad Raddaoui, MD, Abdul-Kareem Almomen, MD, Saleh Al-Muhsen, MD, Raif S. Geha, MD, Fowzan S. Alkuraya, MD Journal of Allergy and Clinical Immunology Volume 130, Issue 2, Pages 481-488.e2 (August 2012) DOI: 10.1016/j.jaci.2012.05.043 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Pedigree of a multiplex consanguineous family with a novel phenotype of CVID, immune dysregulation, or both characterized by IBD. Solid symbols denote affected status. Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Histology of patients' intestinal biopsy specimens. A, Duodenal biopsy specimen from patient VI:2 showing marked villous atrophy and increased chronic inflammatory lymphoplasma cells in the lamina propria (hematoxylin and stain, original magnification ×20). B, High-power view of a duodenal biopsy specimen from patient VI:2 showing increased intraepithelial lymphocytes (arrows; hematoxylin and eosin stain, original magnification ×60). C, Colonic biopsy specimen from patient V:4 (transverse colon) showing a remarkable increase in mixed acute and chronic inflammatory cell numbers in the lamina propria and a decreased number of crypts and fibrosis, mainly subepithelial (arrow; hematoxylin and eosin stain, original magnification ×20). D, High-power view of a colonic biopsy specimen from patient V:4 (transverse colon) showing increased intraepithelial lymphocyte numbers (arrows; hematoxylin and eosin stain, original magnification ×60). Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Filtration scheme of the exome variants identified in patient VI:5. Note the dramatic reduction in the number of candidate variants when filtered by the coordinates of the autozygosity intervals that are exclusively shared between the affected members. Only 1 of the 13 coding/splicing variants was novel (ie, not found in publically available single nucleotide polymorphism databases or our in-house 183 Saudi exomes). Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A, Genomic structure of the LRBA gene. The location of the mutation is denoted by the red bar, and the genomic sequence around it in the patient (Pt) and control subject (NC) is shown under it. B, Schematic structure of the LRBA protein. Note that the truncating mutation removes the BEACH and WD40 domains at the C-terminus, which are functionally important in CHS/LYST. ARM, Armadillo; DUF, domain of unknown function. C, Western blot analysis reveals the absence of the hypothetical 247-kDa truncated LRBA in 2 patients' cell lines compared with the 320-kDa normal LRBA band seen in both control cell lines (NC 1 and NC 2). Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, Lymph node (left axilla) shows marked follicular lymphoid hyperplasia with prominent germinal centers (hematoxylin and eosin stain, original magnification ×20). B, The same lymph node. A CD20 immunohistochemistry stain specific for B cells (Novocastra, Newcastle Upon Tyne, United Kingdom) shows dense staining (CD20 marker, immunohistochemical stain, original magnification ×20). Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 RT-PCR analysis shows no evidence of significant nonsense-mediated decay affecting the aberrant LRBA transcript in patients because it appears to have comparable abundance with the normal transcript seen in control subjects. Journal of Allergy and Clinical Immunology 2012 130, 481-488.e2DOI: (10.1016/j.jaci.2012.05.043) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions