Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes




  1. Stoehr, J.P. et al. Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes 49, 1946–1954 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Bell, G.I. & Polonsky, K.S. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 414, 788–791 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Rhodes, C.J. Type 2 diabetes-a matter of beta-cell life and death? Science 307, 380–384 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Florez, J.C., Hirschhorn, J. & Altshuler, D. The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits. Annu. Rev. Genomics Hum. Genet. 4, 257–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Permutt, M.A., Wasson, J. & Cox, N. Genetic epidemiology of diabetes. J. Clin. Invest. 115, 1431–1439 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Parikh, H. & Groop, L. Candidate genes for type 2 diabetes. Rev. Endocr. Metab. Disord. 5, 151–176 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Barroso, I. et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol. 1, E20 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Clee, S.M., Nadler, S.T. & Attie, A.D. Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes. Am. J. Ther. 12, 491–498 (2005).

    Article  PubMed  Google Scholar 

  9. Hermey, G. et al. Characterization of Sorcs1, an alternatively spliced receptor with completely different cytoplasmic domains that mediate different trafficking in cells. J. Biol. Chem. 278, 7390–7396 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Hampe, W., Rezgaoui, M., Hermans-Borgmeyer, I. & Schaller, H.C. The genes for the human VPS10 domain-containing receptors are large and contain many small exons. Hum. Genet. 108, 529–536 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Hermey, G., Sjogaard, S., Petersen, C.M., Nykjaer, A. & Gliemann, J. Tumour necrosis factor-alpha convertase mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem. J. 395, 285–293 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Song, S., Ewald, A.J., Stallcup, W., Werb, Z. & Bergers, G. PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat. Cell Biol. 7, 870–879 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Abramsson, A., Lindblom, P. & Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Invest. 112, 1142–1151 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lammert, E. et al. Role of VEGF-A in vascularization of pancreatic islets. Curr. Biol. 13, 1070–1074 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Brissova, M. et al. Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53, 1318–1325 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Jacobsen, L. et al. Activation and functional characterization of the mosaic receptor SorLA/LR11. J. Biol. Chem. 276, 22788–22796 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Munck Petersen, C. et al. Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding. EMBO J. 18, 595–604 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Westergaard, U.B. et al. Sorcs3 does not require propeptide cleavage to bind nerve growth factor. FEBS Lett. 579, 1172–1176 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Westergaard, U.B. et al. Functional organization of the sortilin Vps10p-domain. J. Biol. Chem. 279, 50221–50229 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Duggirala, R. et al. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am. J. Hum. Genet. 64, 1127–1140 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Galli, J. et al. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat. Genet. 12, 31–37 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Kim, J.H. et al. Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics 74, 273–286 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Kluge, R. et al. Quantitative trait loci for obesity and insulin resistance (Nob1, Nob2) and their interaction with the leptin receptor allele (LeprA720T/T1044I) in New Zealand obese mice. Diabetologia 43, 1565–1572 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Wiltshire, S. et al. A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am. J. Hum. Genet. 69, 553–569 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei, S. et al. Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat. Mamm. Genome 10, 249–258 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Rabaglia, M.E. et al. Alpha-ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice. Am. J. Physiol. Endocrinol. Metab. 289, E218–E224 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Liu, Y. & Zeng, Z.B. A general mixture model approach for mapping quantitative trait loci from diverse cross designs involving multiple inbred lines. Genet. Res. 75, 345–355 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Zou, F., Yandell, B.S. & Fine, J.P. Statistical issues in the analysis of quantitative traits in combined crosses. Genetics 158, 1339–1346 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Broman, K.W., Wu, H., Sen, S. & Churchill, G.A. R/qtl: QTL mapping in experimental crosses. Bioinformatics 19, 889–890 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Churchill, G.A. & Doerge, R.W. Empirical threshold values for quantitative trait mapping. Genetics 138, 963–971 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Alan D Attie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing