Affiliation:
1. Department of Endocrinology Children's Hospital of Nanjing Medical University Nanjing China
2. Department of Child Healthcare Lianyungang Maternal and Children's Hospital Lianyungang China
3. Nanjing Key Laboratory of Pediatrics Children's Hospital of Nanjing Medical University Nanjing China
Abstract
AbstractBackgroundGermline gain‐of‐function (GOF) variants in the signal transducer and activator of transcription 3 (STAT3) gene lead to a rare inherited disorder characterized by early‐onset multiorgan autoimmunity.MethodsWe described a Chinese patient with infantile‐onset diabetes and multiorgan autoimmunity. The patient presented with early‐onset type 1 diabetes and autoimmune hypothyroidism at 7 months. During the 7.5‐year follow‐up, she developed pseudo‐celiac enteropathy at 1 year of age and showed severe growth retardation. Whole‐exome sequencing was performed and the novel variant was further assessed by in vitro functional assays.ResultsWhole‐exome sequencing revealed a novel variant (c.1069G>A, p.Glu357Lys) in the DNA‐binding domain of STAT3. In vitro functional studies revealed that p.Glu357Lys was a GOF variant by increasing STAT3 transcriptional activity and phosphorylation. In addition, the STAT3 Glu357Lys variant caused dysregulation of insulin gene expression by enhancing transcriptional inhibition of the insulin gene enhancer binding protein factor 1 (ISL1).ConclusionIn the current study, we describe clinical manifestations and identify a novel STAT3 GOF variant (c.1069G>A) in a Chinese patient. This activating variant impairs insulin expression by increasing transcriptional inhibition of its downstream transcription factor ISL1, which could be involved in the pathogenesis of early‐onset diabetes.