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A threonine-to-Isoleucine (Thr 52 Ile) mutation within the pro-domain of the Sorcs1 gene was positionally cloned as the gene underlying a quantitative trait locus that affects fasting insulin levels in mice. In humans, genome-wide association studies and linkage studies have shown that SORCS1 is associated with diabetes and all of diabetes complications. We have recently shown that deletion of  Sorcs1  in mice made obese with the  leptin   ob   mutation results in diabetes and an insulin granule stability defect. This present study investigates the functional consequence of the  Sorcs1  Thr 52 Ile mutation in the rat INS1 β-cell line expressing either the wildtype or mutant Sorcs1 allele. We find that  Sorcs1  Thr 52 Ile mutation is associated with increased basal insulin secretion, reduced glucose-stimulated insulin secretion and decreased insulin content in INS1 cells. Moreover, expression of Thr 52 Ile causes differential processing of the Sorcs1 protein resulting in the formation of an additional 90 kDa mutant form of the protein. The mutant form of the protein is localised to the ER, retains its pro-domain, and concurrently reduces expression of the functional mature 130 kDa Sorcs1 protein. These findings provide a mechanistic clue to why this specific allelic variation in  Sorcs1  was associated with reduced insulin levels and type 2 diabetes.

Type 2 diabetes-associated single nucleotide polymorphism in Sorcs1 gene results in alternative processing of the Sorcs1 protein in INS1 β-cells