Mycobacterial and Candida Infections in a Patient with Novel Dominant Negative Mutation of STAT1 Linker Domain

Abstract

Background and aims: Genetic defects in IFNγ/IL12 pathway causes susceptibility to severe infections with mycobacteria and fungi. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor involved in this signaling pathway. It is crucial in interferon-mediated immunity against microbial infections by regulating the expressions of IFN responsive genes. Chronic mucocutaneous candidiasis is a heterogeneous group of primary immunodeficiency diseases characterised by Candida infections of the skin and oropharynx. STAT1 gainof-function mutation was shown to be responsible for autosomal-dominant cases of chronic candidiasis. In contrast, STAT1 loss-of-function mutations have been mostly reported in patients with atypical mycobacterial and Salmonella infection. Herein we sought to investigate the STAT1 mutation in a patient who presented with not only recurrent candidiasis, but also mycobacterial infection. Methods: Exome sequencing was performed for this patient. After bioinformatical analysis, STAT1 was sequenced by Sanger sequencing. The STAT1 signaling pathway including IFN-stimulated STAT1 phosphorylation, transcriptional response and target gene expressions were examined.

Results: The patient was a Chinese girl born to nonconsanguineous parents. Since infancy she presented with recurrent oropharyngeal and perineal candidiasis that was refractory to antifungal treatment, and also had recurrent Salmonella gastroenteritis. At 5 years old, she developed granulomatous lymphadenitis caused by Mycobacterium fortuitum. At 14 months she developed type 1 diabetes mellitus and was treated with insulin. Exome sequencing identified a novel autosomal dominant loss-of-function E559K mutation in the linker domain of STAT1, which was confirmed by Sanger sequencing. The mutation impaired phosphorylation induced by both IFNγ and IFNα, leading to decreased expressions of interferon inducible target genes. STAT1 protein expression was not affected. Conclusions: In addition to mycobacterial infection, STAT1 loss-of-function mutation also predisposes to chronic mucocutaneous candidiasis, likely through aberrant regulation of IFN-mediated response. This extends the spectrum of clinical phenotype of STAT1 loss-of-function mutation. We also for the first time reported STAT1 mutation in the linker domain.