Introduction: Signal transducers and activators of transcription 1 (STAT1) is a latent DNA binding factor that is activated by tyrosine phosphorylation, following interferon α and γ signaling as well as other signaling molecules. Mutations in STAT1 are associated with a broad spectrum of clinical manifestations, including infections, chronic mucocutaneous candidiasis (CMCC), autoimmunity and cancer.
Aim: To describe a group of patients with time-dependent evolving combined immunodeficiency and chronic colitis, which culminate in fatal viral infections.
Methods: We employed whole exome sequencing, immune evaluation, thymus morphology and immunohistochemistry, and gut pathology.
Results: These patients were found to carry de novo heterozygous mutations in STAT1 encoding T385M, I294T or C284R amino acid substitutions in the DNA binding domain (DBD). STAT1 protein expression appeared significantly decreased in T cells, which had diminished function as well as reduced secretion of IFNγ and IL2. STAT1 phosphorylation was increased in EBV transformed lines from these patients. This group displayed progressive loss in lymphocyte number and function, which was accompanied by increasing autoimmune features, including severe chronic colitis, and fatal infections such as CMV, EBV and JC. Assessment of thymus tissue demonstrated loss of cortico-medullary architecture as well as absent Hassall’s corpuscles, hallmarks of profound T cell deficiency.
Discussion: Heterozygous STAT1 mutations at the DBD are associated with fatal progressive T cell dysfunction. The role of tyrosine phosphorylation abnormalities in this condition requires further elucidation. These results suggest that earlier identification and treatment, such as bone marrow transplant, might prevent the fatal outcome.
