Fig. 1
Diagrammatic representation of the amino acid sequence of human preproinsulin (signal peptide–green, B-chain–red, C-peptide–orange, A-chain–dark blue) indicating sites of mutations identified in patients with diabetes as well as hyperinsulinemia and hyperproinsulinemia. Mutations shown in black disrupt proinsulin folding and/or disulfide bond formation leading to permanent neonatal diabetesmellitus (PNDM); mutations in light blue do not impair folding but are associated with reduced insulin receptor binding potency (hyperinsulinaemia); mutations in light green are associated with hyperproinsulinaemia and either impair proteolytic processing to insulin or, in the case of H34D, aggregation and sorting into dense-core granules of the regulated secretory pathway. Mutations in pink and purple were found in patients with a diagnosis of maturity-onset diabetes of the young (MODY) and type 1b diabetes, respectively. The R55C mutation has been found in patients with a diagnosis of type 1b diabetes as well as MODY. The mutations shown in gray (A23S, A23T, L68M and G84R) are rare variants without functional effects on proinsulin/insulin biosynthesis. The mutations shown in yellow are recessive mutations that affect insulin biosynthesis (mutation of the translation initiation Met) or cause the synthesis of a nonsense protein (Q62X)