A deep intronic splice-altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion.

Autor: Ochoa S; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Hsu AP; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Oler AJ; Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD 20892, USA., Kumar D; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA., Chauss D; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA., van Hamburg JP; Departments of Rheumatology and Clinical Immunology and Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, Netherlands., van Laar GG; Departments of Rheumatology and Clinical Immunology and Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, Netherlands., Oikonomou V; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Ganesan S; Biological Imaging Section, Research Technologies Branch, NIAID, NIH, Bethesda, MD 20892, USA., Ferré EMN; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Schmitt MM; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., DiMaggio T; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Barber P; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Constantine GM; Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA., Rosen LB; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Auwaerter PG; Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Gandhi B; Division of Internal Medicine-Pediatrics, Department of Medicine, Medstar Georgetown University Hospital, Washington, DC 20007, USA., Miller JL; Division of Pediatric Endocrinology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA., Eisenberg R; Division of Allergy and Immunology, Department of Pediatrics, Montefiore Medical Center, Bronx, NY 10467, USA., Rubinstein A; Division of Allergy and Immunology, Department of Pediatrics, Montefiore Medical Center, Bronx, NY 10467, USA.; Department of Microbiology and Immunology, Montefiore Medical Center, Bronx, NY 10467, USA., Schussler E; Division of Pulmonary, Allergy, and Immunology, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA., Balliu E; Department of Endocrinology, Diabetes and Metabolism, Lakeland Regional Health Grasslands Campus, Lakeland, FL 33803, USA., Shashi V; Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.; Undiagnosed Diseases Network, Duke University Medical Center, Durham, NC 27710, USA., Neth O; Inborn Errors of Immunity Laboratory, Biomedicine Institute in Seville (IBiS), University of Seville/CSIC, 'Red de Investigación Translacional en Infectología Pediátrica,' Paediatric Infectious Diseases, Rheumatology and Immunology Unit, Virgen del Rocío University Hospital, Seville 41013, Spain., Olbrich P; Inborn Errors of Immunity Laboratory, Biomedicine Institute in Seville (IBiS), University of Seville/CSIC, 'Red de Investigación Translacional en Infectología Pediátrica,' Paediatric Infectious Diseases, Rheumatology and Immunology Unit, Virgen del Rocío University Hospital, Seville 41013, Spain.; Departamento de Farmacología, Pediatría y Radiología, Facultad de Medicina, Universidad de Sevilla, Seville 41004, Spain., Le KM; Translational Immunology Research Program, University of Helsinki, Helsinki 00014, Finland.; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00290, Finland., Mamia N; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00290, Finland., Laakso S; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00290, Finland.; Folkhälsan Research Center, Helsinki 00250, Finland.; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland., Nevalainen PI; JJP Biologics, Warsaw 00-728, Poland., Grönholm J; Translational Immunology Research Program, University of Helsinki, Helsinki 00014, Finland.; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00290, Finland., Seppänen MRJ; Translational Immunology Research Program, University of Helsinki, Helsinki 00014, Finland.; Pediatric Research Center, New Children's Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki 00290, Finland.; European Reference Network Rare Immunodeficiency Autoinflammatory and Autoimmune Diseases Network (ERN RITA) Core Center, Utrecht, 3584 CX, Netherlands., Boon L; JJP Biologics, Warsaw 00-728, Poland., Uzel G; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Franco LM; Functional Immunogenomics Unit, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA., Heller T; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA., Winer KK; Pediatric Growth and Nutrition Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA., Ghosh R; Centralized Sequencing Program, Division of Intramural Research, NIAID, NIH, Bethesda, MD 20892, USA., Seifert BA; Centralized Sequencing Program, Division of Intramural Research, NIAID, NIH, Bethesda, MD 20892, USA., Walkiewicz M; Centralized Sequencing Program, Division of Intramural Research, NIAID, NIH, Bethesda, MD 20892, USA., Notarangelo LD; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Zhou Q; Inflammatory Disease Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA., Askentijevich I; Inflammatory Disease Section, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA., Gahl W; Medical Genetics Branch, National Human Genome Research Institute, and NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA., Dalgard CL; Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.; American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA., Perera L; Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA., Afzali B; Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA., Tas SW; Departments of Rheumatology and Clinical Immunology and Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1105 AZ, Netherlands., Holland SM; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Lionakis MS; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Sep 18; Vol. 16 (765), pp. eadk0845. Date of Electronic Publication: 2024 Sep 18.
DOI: 10.1126/scitranslmed.adk0845
Abstrakt: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator ( AIRE ) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE -expressing primary patient monocyte-derived dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE -expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE -transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.
Databáze: MEDLINE