Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies

OBJECTIVE—Heterozygous, gain-of-function mutations of the insulin gene can cause permanent diabetes with onset ranging from the neonatal period through adulthood. The aim of our study was to screen for the insulin gene in patients who had been clinically classified as type 1 diabetic but who tested negative for type 1 diabetes autoantibodies.RESEARCH DESIGN AND METHODS—We reviewed the clinical records of 326 patients with the diagnosis of type 1 diabetes and identified seven probands who had diabetes in isolation and were negative for five type 1 diabetes autoantibodies. We sequenced the INS gene in these seven patients.RESULTS—In two patients whose diabetes onset had been at 2 years 10 months of age and at 6 years 8 months of age, respectively, we identified the mutation G^B8S and a novel mutation in the preproinsulin signal peptide (A^Signal23S).CONCLUSIONS—Insulin gene mutations are rare in absolute terms in patients classified as type 1 diabetic (0.6%) but can be identified after a thorough screening of type 1 diabetes autoantibodies.Mutations of the insulin (INS) gene associated with neonatal- and infancy-onset diabetes cause sustained stress of the endoplasmic reticulum, which in turn triggers apoptosis of the pancreatic β-cell (1). In patients with insulin mutations with proteotoxic effect, diabetes presents in isolation and the onset of hyperglycemia may occur well outside the neonatal period (1–4). As a consequence, individuals with INS gene mutations may be confused with patients having autoimmune type 1 diabetes (1–4).