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Positional Cloning of Zinc Finger Domain Transcription Factor Zfp69, a Candidate Gene for Obesity-Associated Diabetes Contributed by Mouse Locus Nidd/SJL

Stephan Scherneck1, Matthias Nestler1, Heike Vogel1, Matthias Blüher2, Marcel-Dominique Block1, Mauricio Berriel Diaz3, Stephan Herzig3, Nadja Schulz1, Marko Teichert1, Sina Tischer1, Hadi Al-Hasani1, Reinhart Kluge1, Annette Schürmann1, Hans-Georg Joost1*

1 Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany, 2 Department of Medicine, University of Leipzig, Leipzig, Germany,

3 Emmy Noether and Marie Curie Research Group Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany

Abstract Top

Polygenic type 2 diabetes in mouse models is associated with obesity and results from a combination of adipogenic and diabetogenic alleles. Here we report the identification of a candidate gene for the diabetogenic effect of a QTL (Nidd/SJL, Nidd1) contributed by the SJL, NON, and NZB strains in outcross populations with New Zealand Obese (NZO) mice. A critical interval of distal chromosome 4 (2.1 Mbp) conferring the diabetic phenotype was identified by interval-specific congenic introgression of SJL into diabetes-resistant C57BL/6J, and subsequent reporter cross with NZO. Analysis of the 10 genes in the critical interval by sequencing, qRT–PCR, and RACE–PCR revealed a striking allelic variance of Zfp69 encoding zinc finger domain transcription factor 69. In NZO and C57BL/6J, a retrotransposon (IAPLTR1a) in intron 3 disrupted the gene by formation of a truncated mRNA that lacked the coding sequence for the KRAB (Krüppel-associated box) and Znf-C2H2 domains of Zfp69, whereas the diabetogenic SJL, NON, and NZB alleles generated a normal mRNA. When combined with the B6.V-Lepob background, the diabetogenic Zfp69SJL allele produced hyperglycaemia, reduced gonadal fat, and increased plasma and liver triglycerides. mRNA levels of the human orthologue of Zfp69, ZNF642, were significantly increased in adipose tissue from patients with type 2 diabetes. We conclude that Zfp69 is the most likely candidate for the diabetogenic effect of Nidd/SJL, and that retrotransposon IAPLTR1a contributes substantially to the genetic heterogeneity of mouse strains. Expression of the transcription factor in adipose tissue may play a role in the pathogenesis of type 2 diabetes.

Author Summary Top
Type 2 diabetes in humans as well as in obese mice is caused by a combination of adipogenic and diabetogenic gene variants. We have identified a gene that appears to be involved in the pathogenesis of hyperglycaemia in obese mice: in some mouse strains, the gene Zfp69 is disrupted by a retroviral transposon (IAPLTR1a), which generates a truncated mRNA. Disruption of the gene was associated with a reduced susceptibility for diabetes, whereas the normal allele enhanced hyperglycaemia in obese mice. Zfp69 encodes a transcription factor which appears to interfere with lipid storage in adipose tissue, and thereby enhances lipid deposition in liver. In humans with type 2 diabetes, mRNA levels of the human orthologue of Zfp69 (ZNF642) were increased in adipose tissue. Thus, the transcription factor ZFP69/ZNF642 may be involved in the pathogenesis of obesity-associated diabetes.

Citation: Scherneck S, Nestler M, Vogel H, Blüher M, Block M-D, et al. (2009) Positional Cloning of Zinc Finger Domain Transcription Factor Zfp69, a Candidate Gene for Obesity-Associated Diabetes Contributed by Mouse Locus Nidd/SJL. PLoS Genet 5(7): e1000541. doi:10.1371/journal.pgen.1000541

Editor: Jonathan Flint, The Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom

Received: March 11, 2009; Accepted: June 1, 2009; Published: July 3, 2009

Copyright: © 2009 Scherneck et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The study was supported by grants from the European Union (EUGENE2 LSHM-CT-2004-512013, www.eugene2.com) and the German Bundesministerium für Bildung und Forschung (NGFN-Plus 01GS0821 and NGFN2 01GS0487, www.bmbf.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: joost@dife.de



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