Gene ID'd in Autoinflammatory Syndrome in Children
(HealthDay News) — A candidate gene has been identified in a new autoinflammatory syndrome in children, according to a study published online July 16 in the New England Journal of Medicine.
Yu Lin, M.D., PhD, from the National Institutes of Health in Bethesda, Md., and colleagues analyzed DNA from an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. In this patient and five unrelated children with similar clinical phenotypes, a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING) was sequenced. Clinical and immunological evaluations were conducted for four of the children.
In all six patients, the researchers identified three mutations in exon 5 of TMEM173. In peripheral blood mononuclear cells from the patients, elevated transcription of IFNB1 and other gene targets of STING indicated constitutive activation of the pathway that can only be further up-regulated with stimulation. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulation correlated with increased transcription of IFNB1, but not of the genes encoding interleukin-1, interleukin-6, or tumor necrosis factor, in fibroblasts from patients. Elevated IFNB1 reporter levels were identified in HEK293T cells transfected with mutant STING constructs. Endothelial cells were found to express STING, and exposure to cGAMP triggered endothelial activation and apoptosis in these cells.
"STING-associated vasculopathy with onset in infancy is an autoinflammatory disease caused by gain-of-function mutations in TMEM173," the authors write.