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Human Molecular Genetics Advance Access originally published online on August 7, 2006
Human Molecular Genetics 2006 15(18):2732-2742; doi:10.1093/hmg/ddl209
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification of the transcription factor ARNTL2 as a candidate gene for the type 1 diabetes locus Idd6

Ming-Shiu Hung{dagger}, Philip Avner and Ute Christine Rogner*

Unité de Génétique Moléculaire Murine CNRS URA 2578, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, Cedex 15, France

* To whom correspondence should be addressed. Tel: +33 145688602; Fax: +33 145688656; Email: urogner{at}pasteur.fr

Received July 3, 2006; Accepted July 31, 2006

The Idd6 murine type 1 diabetes locus has been shown to control diabetes by regulating the protective activity of the peripheral immune system, as demonstrated by diabetes transfer assays using splenocytes. The analysis of three novel subcongenic (NOD.C3H nonobese. C3H) diabetes strains has confirmed the presence of at least two diabetes-related genes within the 5.8 Mb Idd6 interval with the disease protection conferred by splenocyte co-transfer being located to the 700 kb Idd6.3 subregion. This subinterval contains the circadian rhythm-related transcription factor Arntl2 (Bmal2), a homologue of the type 2 diabetes-associated ARNT (HIF1ß) gene. Arntl2 exhibited a six-fold upregulation in spleens of the NOD.C3H 6.VIII congenic strain compared with the NOD control strain, strain-specific splice variants and a large number of polymorphisms in both coding and non-coding regions. Arntl2 upregulation was not associated with changes in the expression levels of other circadian genes in the spleen, but did correlate with the upregulation of the ARNT-binding motif containing Pla2g4a gene, which has recently been described as being protective for the progression of insulitis and autoimmune diabetes in the NOD mouse via regulation of the tumour necrosis factor-alpha pathway. Our studies strongly suggest that the HIFß-homologous Arntl2 gene is involved in the control of type 1 diabetes.

{dagger} Present address: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli 350, Taiwan.


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