Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis

作者：Breuer Oded^*; Daum Hagit; Cohen Cymberknoh Malena; Unger Susanne; Shoseyov David; Stepensky Polina; Keller Baerbel; Warnatz Klaus; Kerem Eitan

来源：Respiratory Medicine, 2017, 126: 39-45.

DOI：10.1016/j.rmed.2017.03.018

• Bronchiectasis
• Chronic mucocutaneous candidiasis
• Autosomal dominant gain-of-function
• STAT1 mutations (AD-GOF STAT1 mutations)
• Memory B cells

Background: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown.
Objective: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis.
Methods: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping.
Results: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD-GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon g (IFN-g). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen.
Conclusions: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD-GOF mutations in STAT1 to suppurative sinopulmonary disease.

• 出版日期2017-5