Human Molecular Genetics Advance Access originally published online on August 7, 2006
Human Molecular Genetics 2006 15(18):2709-2720; doi:10.1093/hmg/ddl204
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition
1 Myriad Genetics, Inc., Salt Lake City, 320 Wakara Way, UT 84108, USA, 2 Department of Psychiatry, Genome Research Institute, University of Cincinnati, OH 45237, USA, 3 Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA and 4 Cardiovascular Genetics, Department of Medicine, University of Utah, Salt Lake City, UT 84108, USA
* To whom correspondence should be addressed. Tel: +1 8015843695; Fax: +1 8015843640; Email: sstone{at}myriad.com
Received June 8, 2006; Accepted July 28, 2006
The molecular etiology of obesity predisposition is largely unknown. Here, we present evidence that genetic variation in TBC1D1 confers risk for severe obesity in females. We identified a coding variant (R125W) in TBC1D1 that segregated with the disease in 4p15–14-linked obesity pedigrees. In cases derived from pedigrees with the strongest linkage evidence, the variant was significantly associated with obesity (P=0.000007) and chromosomes carrying R125W accounted for the majority of the evidence that originally linked 4p15–14 with the disease. In addition, by selecting families that segregated R125W with obesity, we were able to generate highly significant linkage evidence for an obesity predisposition locus at 4q34–35. This result provides additional and confirming evidence that R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34–35 and identifies a gene/gene interaction that influences the risk for obesity predisposition. Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin-mediated Glut4 translocation.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. R. Peck, J. A. Chavez, W. G. Roach, B. A. Budnik, W. S. Lane, H. K. R. Karlsson, J. R. Zierath, and G. E. Lienhard Insulin-stimulated Phosphorylation of the Rab GTPase-activating Protein TBC1D1 Regulates GLUT4 Translocation J. Biol. Chem., October 30, 2009; 284(44): 30016 - 30023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E Leney and J. M Tavare The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets J. Endocrinol., October 1, 2009; 203(1): 1 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pehmoller, J. T. Treebak, J. B. Birk, S. Chen, C. MacKintosh, D. G. Hardie, E. A. Richter, and J. F. P. Wojtaszewski Genetic disruption of AMPK signaling abolishes both contraction- and insulin-stimulated TBC1D1 phosphorylation and 14-3-3 binding in mouse skeletal muscle Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E665 - E675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.J. Ireland, A.E. Zielak-Steciwko, F. Jimenez-Krassel, J. Folger, A. Bettegowda, D. Scheetz, S. Walsh, F. Mossa, P.G. Knight, G.W. Smith, et al. Variation in the Ovarian Reserve Is Linked to Alterations in Intrafollicular Estradiol Production and Ovarian Biomarkers of Follicular Differentiation and Oocyte Quality in Cattle Biol Reprod, May 1, 2009; 80(5): 954 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Sakamoto and G. D. Holman Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E29 - E37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Meyre, M. Farge, C. Lecoeur, C. Proenca, E. Durand, F. Allegaert, J. Tichet, M. Marre, B. Balkau, J. Weill, et al. R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population Hum. Mol. Genet., June 15, 2008; 17(12): 1798 - 1802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. B. Taylor, D. An, H. F. Kramer, H. Yu, N. L. Fujii, K. S. C. Roeckl, N. Bowles, M. F. Hirshman, J. Xie, E. P. Feener, et al. Discovery of TBC1D1 as an Insulin-, AICAR-, and Contraction-stimulated Signaling Nexus in Mouse Skeletal Muscle J. Biol. Chem., April 11, 2008; 283(15): 9787 - 9796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Roman, D. A. Benitez, J. M. Carvajal-Gonzalez, and P. M. Fernandez-Salguero Genome-wide B1 retrotransposon binds the transcription factors dioxin receptor and Slug and regulates gene expression in vivo PNAS, February 5, 2008; 105(5): 1632 - 1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. I. Welsh, S. E. Leney, B. Lloyd-Lewis, M. Wherlock, A. J. Lindsay, M. W. McCaffrey, and J. M. Tavare Rip11 is a Rab11- and AS160-RabGAP-binding protein required for insulin-stimulated glucose uptake in adipocytes J. Cell Sci., December 1, 2007; 120(23): 4197 - 4208. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Yang, T. Kelly, and J. He Genetic Epidemiology of Obesity Epidemiol. Rev., June 12, 2007; (2007) mxm004v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S Fisler and C. H Warden The current and future search for obesity genes Am. J. Clinical Nutrition, January 1, 2007; 85(1): 1 - 2. [Full Text] [PDF]
|
|