A functional missense variant in MRI1 links methionine salvage to reduced type 2 diabetes risk

Type 2 diabetes (T2D) pathogenesis is shaped by both risk and protective genetic variants, but mechanisms underlying disease protection remain understudied. Previously, in a population isolate with high T2D prevalence, we unexpectedly identified a relatively frequent protective missense variant (Arg149Cys, rs551664067 C/T) in the methionine salvage gene MRI1, never reported for T2D. MRI1 is expressed in human pancreatic islets and insulin-responsive tissues, with islet expression correlating with insulin expression. Using MRI1’s resolved crystal structure, we show Arg149Cys substitution compacts the ligand-binding pocket by >53%, and enzyme kinetics confirm enhanced substrate engagement and 18.6% improved catalytic flux, boosting methionine salvage for downstream pathway enzymes. Circulating methionine levels inversely correlated with insulin sensitivity, consistent with enhanced MRI1 activity channeling methionine into salvage rather than pathological accumulation. Together, MRI1 is identified as a metabolic regulator that links enzyme biophysics to efficient methionine recycling and T2D protection, showcasing quantitative NMR as a genetics-to-mechanism bridge.