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

Nature Genetics volume 38, pages 688–693 (2006)Cite this article

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) mice1. 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.

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Figure 1: Impaired pancreatic function in 1339AB6/B6 mice.
Figure 2: Disrupted islet morphology in 1339AB6/B6 mice.
Figure 3: Refinement of the T2dm2 QTL location with interval-specific congenic mouse strains.
Figure 4: Sorcs1 coding mutations and expression differences.

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Acknowledgements

This work was supported by US National Institute of Diabetes and Digestive and Kidney Diseases grants 58037 and 66369 to A.D.A.; American Heart Association postdoctoral fellowships 0325480Z and 0525688Z to S.M.C.; grants from the US Department of Agriculture's Cooperative State Research, Education and Extension Service to B.S.Y. and A.D.A.; a Sponsored Research Agreement with Xenon Pharmaceuticals (formerly Xenon Genetics) and an American Diabetes Association Mentor-Based Fellowship to A.D.A. We thank W.F. Dove for his advice and encouragement throughout this project, A. Steinberg for his expert assistance in preparing the figures for this manuscript and the staff in our animal care facility for their dedication to this work.

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Authors and Affiliations

  1. Department of Biochemistry, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Susanne M Clee, Kathryn M Schueler, Mary E Rabaglia, Oliver C Richards, Summer M Raines, Edward A Kabara, Daniel M Klass, Eric T-K Mui, Donald S Stapleton, Mark P Gray-Keller, Matthew B Young, Jonathan P Stoehr, Hong Lan, Igor Boronenkov, Philipp W Raess, Matthew T Flowers & Alan D Attie

  2. Department of Horticulture, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Brian S Yandell

  3. Department of Statistics, University of Wisconsin-Madison, Madison, 53706, Wisconsin, USA

    Brian S Yandell

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Correspondence to Alan D Attie.

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Supplementary information

Supplementary Table 1

Phenotypic characterization of female 1339A congenic mice. (PDF 21 kb)

Supplementary Table 2

Sequence and expression analysis of genes in the 1339A strain. (PDF 30 kb)

Supplementary Table 3

Primers used for sequencing, quantitative RT-PCR and marker genotyping. (PDF 22 kb)

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Clee, S., Yandell, B., Schueler, K. et al. Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat Genet 38, 688–693 (2006). https://doi.org/10.1038/ng1796

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