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PAX1 is essential for development and function of the human thymus.

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机构： [1]Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA [2]Human and Molecular Genetics Center, Medical College Wisconsin, Milwaukee,MI, USA [3]Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD 20892, USA [4]Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy [5]Cytogenetic and Medical Genetics Unit, “A.Nocivelli” Institute for Molecular Medicine, Spedali Civili Hospital, Brescia, Italy [6]Coyote Bioscience USA Inc.,San Jose, CA95138, USA [7]Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA [8]Departmentof Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia [9]Saudi Human Genome Program, King Abdulaziz City for Science and Technology,Riyadh, Saudi Arabia [10]Division of Pediatric Allergy and Immunology, Mayo Clinic Children’s Center, Rochester, MN, USA [11]Genomic Technologies Section, NIAID, NIH,Bethesda, MD 20892, USA [12]Research Technologies Branch, DIR, NIAID, NIH, Bethesda, MD 20892, USA [13]Department of Medical and Surgical Specialties, RadiologicalSciences and Public Health, University of Brescia, Brescia, Italy [14]Department of Radiology, Mayo Clinic, Rochester, MN, USA [15]Alfaisal University, Riyadh, Saudi Arabia [16]GeneDx Inc.,Gaithersburg, MD 20877, USA [17]PerkinElmer Genomics, Pittsburgh, PA 15275, USA [18]Department of Geriatrics, West China Hospital, Sichuan University,Chengdu, China [19]Aperiomics Inc.,Sterling, VA 20166, USA [20]Cancer and Blood Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati Collegeof Medicine, Cincinnati, OH 45229, USA [21]St.Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065,USA [22]Laboratory of Human Genetics of Infectious Diseases, Necker Branch INSERM, Necker Hospital for Sick Children, Paris, France [23]Paris Descartes University, ImagineInstitute, Paris, France [24]Pediatric Immunology, Department of Health Sciences, University of Florence, Florence, Italy [25]Meyer Children’s Hospital, Florence, Italy [26]Department of Pediatrics, Allergy and Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia [27]Pediatrics Hematology-ImmunologyUnit, Necker Hospital for Sick Children, Paris, France [28]Howard Hughes Medical Institute, New York, NY 10065, USA [29]Department of Laboratory Medicineand Pathology, Mayo Clinic, Rochester, MN 55905, USA [30]Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA

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We investigated the molecular and cellular basis of severe combined immunodeficiency (SCID) in six patients with otofaciocervical syndrome type 2 who failed to attain T cell reconstitution after allogeneic hematopoietic stem cell transplantation, despite successful engraftment in three of them. We identified rare biallelic PAX1 rare variants in all patients. We demonstrated that these mutant PAX1 proteins have an altered conformation and flexibility of the paired box domain and reduced transcriptional activity. We generated patient-derived induced pluripotent stem cells and differentiated them into thymic epithelial progenitor cells and found that they have an altered transcriptional profile, including for genes involved in the development of the thymus and other tissues derived from pharyngeal pouches. These results identify biallelic, loss-of-function PAX1 mutations as the cause of a syndromic form of SCID due to altered thymus development. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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大类 | 1 区

医学

小类 | 1 区免疫学

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大类 | 1 区

医学

小类 | 1 区免疫学

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第一作者机构： [1]Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD 20892, USA

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