Fatal combined immunodeficiency associated with heterozygous mutation in STAT1

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Sharfe, Nigel^1,2  Nahum, Amit^3,4  Newell, Andrea^1,2  Dadi, Harjit^1,2  Ngan, Bo⁵  Pereira, Sergio L.⁶  Herbrick, Jo-Anne⁶  Roifman, Chaim M.^1,2,3 

[1] Hosp Sick Children, Div Immunol & Allergy, Canadian Ctr Primary Immunodeficiency, Jeffrey Modell Res Lab Diag Primary Immunodeficie, Toronto, ON M5G 1X8, Canada

[2] Univ Toronto, Toronto, ON, Canada

[3] Hebrew Univ Jerusalem, Canada Israel Immunodeficiency Res Alliance, IL-76100 Rehovot, Israel

[4] Hebrew Univ Jerusalem, Kaplan Med Ctr, IL-76100 Rehovot, Israel

[5] Hosp Sick Children, Div Pathol, Dept Pediat Lab Med, Toronto, ON M5G 1X8, Canada

[6] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada

关键词: Combined immunodeficiency;    STAT1;    mutation;   

DOI  :  10.1016/j.jaci.2013.09.032

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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