Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

Abstract

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.

SORCS1: A Novel Human Type 2 Diabetes Susceptibility Gene Suggested by the Mouse

“…Our studies in the mice localized the causative variant(s) to a region of 242 kb spanning part of the promoter and first exons of the gene (14). To first test the hypothesis that variation in the human SORCS1 gene contributes to fasting insulin levels in the MACAD population, we chose to focus on this same region of the gene.…”

“…Using interval-specific congenic mouse strains, we recently identified SorCS1 as the gene underlying T2dm2 (14). Genetic variation in SorCS1 had its most dramatic effect in obese female mice, where it led to decreased fasting insulin levels via reduced insulin secretion following a glucose challenge and pancreatic islet disruption; insulin sensitivity was not affected.…”

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…For example, SORLA is produced in adipose tissue and in smooth muscle cells 6,13 . Sortilin is found in hepatocytes 14 , while SORCS1 is expressed in pancreatic islets 15 . In contrast to the situation in the nervous system, the expression patterns for VPS10P domain receptors in peripheral tissues are largely non-overlapping suggesting unique functions for each receptor in cardiovascular and metabolic processes.…”

“…This locus has been mapped as a quantitative trait locus affecting fasting insulin levels in obese mice 15 .…”

“…Because SORCS1 is expressed in pancreatic islet cells and expression is increased 10-fold in mice susceptible to T2D 15 , a function for this receptor in insulin secretion from β-cells seems plausible. This hypothesis is supported by studies in Sorcs1 null mice in which loss of SORCS1 coincides with an insulin secretory dysfunction.…”