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

• Published in: Nature genetics Vol. 38; no. 6; pp. 688 - 693
• Main Authors: Attie, Alan D, Clee, Susanne M, Yandell, Brian S, Schueler, Kathryn M, Rabaglia, Mary E, Richards, Oliver C, Raines, Summer M, Kabara, Edward A, Klass, Daniel M, Mui, Eric T-K, Stapleton, Donald S, Gray-Keller, Mark P, Young, Matthew B, Stoehr, Jonathan P, Lan, Hong, Boronenkov, Igor, Raess, Philipp W, Flowers, Matthew T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.06.2006
• Subjects: Amino acids; Animals; Binding sites; Biological and medical sciences; Causes of; Chromosomes; Cloning; Cloning, Molecular; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Gene mapping; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Genotype & phenotype; Glucose Tolerance Test; Health aspects; Insulin - blood; Insulin - metabolism; Insulin Secretion; Medical sciences; Methods; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Obesity; Physiological aspects; Quantitative Trait Loci; Receptors, Cell Surface - genetics; Rodents; Type 2 diabetes; United States; Endocrinopathy; Type 2 diabetes; Metabolic diseases; Molecular cloning; Quantitative character
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1796

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.