Fatal combined immunodeficiency associated with heterozygous mutation in STAT1

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 3; pp. 807 - 817
• Main Authors: Sharfe, Nigel, PhD, Nahum, Amit, MD, PhD, Newell, Andrea, BSc, Dadi, Harjit, PhD, Ngan, Bo, MD, Pereira, Sergio L., PhD, Herbrick, Jo-Anne, BSc, Roifman, Chaim M., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2014; Elsevier
• Subjects: Adolescent; Allergy and Immunology; Biological and medical sciences; Child; Child, Preschool; Combined immunodeficiency; fas Receptor - analysis; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Heterozygote; Humans; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - mortality; Immunopathology; Male; Medical sciences; Mutation; Mycobacterium; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; STAT1; STAT1 Transcription Factor - analysis; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - physiology; Interleukin; Peripheral blood lymphocyte; PHA; mRNA; Phytohemagglutinin; IFN; BSA; Messenger RNA; Combined immunodeficiency; CMCC; Deoxyribonucleic acid; Peripheral blood mononuclear cell; EBV; Epstein-Barr virus; PBL; Enzyme-linked immunosorbent assay; PBS; Bovine serum albumin; Cytomegalovirus; Polyacrylamide gel electrophoresis; IL; Chronic mucocutaneous candidiasis; STAT1; BCG; Phosphate-buffered saline [solution]; Signal transducer and activator of transcription 1; PAGE; Forkhead box P3; CMV; FOXP3; PBMC; mutation; Bacillus Calmette–Guérin; Natural killer; DNA; JC; Interferon; Jamestown Canyon virus; NK; ELISA; Transcription factor STAT1; Immunopathology; Association; Immunology; Genetics; Mutation; Combined immune deficiency; Combined immunodeifciency; Heterozygosity
• DOI: 10.1016/j.jaci.2013.09.032
• ISSN: 0091-6749

Background Mutations in the gene for the signal transducer and activator of transcription 1, STAT1, have been shown to be associated with death at an early age due to overwhelming viral infection (complete STAT1 deficiency) or, more commonly, selective deficiencies to mycobacterial or fungal infection (typically heterozygous STAT1 mutations). Objectives To define the molecular basis of progressive combined immunodeficiency in a group of patients with fatal infections. Methods We studied a group of unrelated patients who displayed an unusual progressive form of combined immunodeficiency. Whole exome sequencing assisted in confirming a common genetic defect in this group, which consisted of a heterozygous mutation of the STAT1 gene. STAT1 protein level as well as function was assessed, and a detailed evaluation of the immune system, including analysis of thymus tissue, was performed. Results Patients were found to carry de novo heterozygous mutations in STAT1 encoding T385A, I294T, or C284R amino acid substitutions. STAT1 expression appeared significantly decreased as a result of these changes but not completely absent, with diminished signaling responses. This group display progressive loss in lymphocyte number and function accompanied by increasing autoimmune features as well as severe, fatal infections. Conclusions These findings show that some heterozygous aberrations of STAT1 can be associated with progressive combined immunodeficiency, quite distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations. These mutations were not inherited, rather, arose de novo in each case. Accompanied by significant patient mortality, this finding suggests that this class of STAT1 mutation is ultimately fatal due to overwhelming infection.