FURIN R81C variant: a link to type 2 diabetes via impaired enzymatic activity

Furin, a proprotein convertase, regulates glucose homeostasis by processing the insulin receptor (IR) precursor. Although the association of furin genetic variants with cardiac and neuronal diseases is well-established, studies investigating the association with type 2 diabetes (T2D) are scarce. This study aimed to examine the association of furin variants with T2D in an Arab cohort. In addition, it sought to elucidate the functional impact of these diabetes-associated variants on furin stability and kinetic activity. Of the 15 rare missense variants in furin identified in global genomic studies, only one, rs148110342_C > T_(R81C), was found in our study cohort, with a minor allele frequency of 2.4%. Allele-based association testing, adjusted for age, sex, and body mass index, revealed significant associations between the rs148110342 and being T2D and borderline associations with fasting plasma glucose and HbA1c levels. Enzyme kinetic studies showed that the R81C variant has higher <i>K</i>_m values, indicating lower enzymatic activity compared with wild-type furin. In silico structural modeling of the interactions between the R81C variant prodomain and the furin catalytic subunit revealed an increase in hydrogen bonding, which might explain the observed reduction in enzymatic activity. Furthermore, cell culture studies suggested that the R81C variant impairs furin's autocatalytic processing and its ability to cleave the precursor insulin receptor. A significant reduction in phosphorylation of ERK1/2 and AKT occurred in HEPG2 cells transfected with R81C variants, suggesting a downregulation of the IR signaling pathway. These findings suggest that the furin R81C variant can potentially impact insulin signaling and thereby contribute to T2D pathogenesis.<b>NEW & NOTEWORTHY</b> This study contributes novel insights into the role of furin variants in T2D risk. The rare rs148110342_C > T_(R81C) variant of furin exhibits a minor allele frequency of 2.4% in Arabs. We observed significant associations between the variant and being diabetic. The variant furin revealed lower enzyme kinetic activity, impairment of furin's autocatalytic processing, and a significant reduction in ERK1/2 and AKT phosphorylation. These findings suggest that the variant downregulates the IR signaling pathway.