Insulin-dependent diabetes (IDDM):

Genetic factors on mouse chromosome 6

Philip Avner, Agnès Lehuen*, Christian Boitard*, Ute Christine Rogner

& Basile Lebailly, Chenxia He°°, Corinne Veron, Isabelle Tardivel*, Yannick Simoni*

former members : David Vallois*, Ming-Shiu Hung° & Joëlle Morin*

Type 1 or insulin-dependent diabetes (T1D, IDDM) is an autoimmune disorder of glucose homeostasis characterized by the progressive destruction of the insulin producing beta-cells of the pancreas. The disease affects about 0.3% of the Caucasian population and the onset is usually before the age of 17 years. The development of IDDM depends not only on environmental factors, but also on genetic factors. Although twenty different genetic loci have been associated with IDDM, most of these genes are not yet identified.
 

The non-obese diabetic (NOD) mouse is a model for the autoimmune disease IDDM. As in human, the development of IDDM is dependent on the interaction of multiple genes, including genes within the Major Histocompatibility Complex and the insulin gene.

Distal mouse chromosome 6 contains several loci conferring susceptibility or resistance to type I diabetes: Idd6, Idd19 and Idd20. Our recent experiments have shown that these three loci interact genetically to influence the onset and final incidence of type I diabetes.

Congenic strains play a pivotal role in our experimental approach to disease candidate gene identification. These mice were derived by transferring the distal chromosome 6 region from the diabetes resistant C3H/HeJ mouse onto the genetic NOD/Lt strain background through repetitive backcrossing.

Our projects are aimed at the identification of the underlying disease related genes and studies on their specific role in the onset of autoimmune disease.

Our experimental approach is genetically based and includes the detailed immunological analysis of congenic strains, transcriptional profiling by microarray hybridisation and real-time PCR, and mutational analysis.

Functional testing of selected candidate genes is performed using RNA interference, overexpression studies and transgenesis.

Recent research progress:

The original genotyping of the congenic strain NOD.C3H 6.VIII indicated that the C3H/HeJ derived donor sequence at Idd6 was limited to 5.8 Megabases at the distal end of chromosome 6. In order to further refine the type 1 diabetes associated Idd6 candidate region, we have constructed three subcongenic strains (6.VIIIa, b, c). All three strains showed diabetes resistance. The corresponding three subcongenic C3H intervals (Idd6.1, Idd6.2, Idd6.3) were defined using a panel of genetic markers for distal chromosome 6. The smallest of the three T1D associated interval identified in our studies is Idd6.3. Within the only 700 kb of Idd6.3 we have identified as a very promising candidate gene, encoding the transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2). Arntl2 is a homologue of the type 2 diabetes-associated ARNT (HIF1ß) gene and is strongly downregulated and altered in the NOD/Lt mouse as compared to the C3H/HeJ mouse. We hypothesize that other type 1 diabetes associated genes are regulated by Arntl2 and that by this mechanism Arntl2 influences diabetes development. see also the publications list ; latest work: Poster EASD meeting 2012.
Although we have identified this promising candidate for Idd6.3, from our analysis we expect to find other T1D associated genes within Idd6. Sequencing of the interval in the NOD/Lt mouse and C3H/HeJ mouse will permit the complete mutational analysis of all the gene content.

 

Unité Génétique Moléculaire Murine, Institut Pasteur, Paris

in collaboration with:

* INSERM U986, St. Vincent de Paul Hospital, Paris

Francina Langa et al. Plate-Forme Technologique Centre d'Ingénierie Génétique Murine, Institut Pasteur

Pierre Charneau et al., Virologie Moléculaire et de Vectorologie, Institut Pasteur

Cécile Julier et al., Unité Postulante de Génétique des Maladies infectieuses et autoimmunes, Institut Pasteur

° current address: National Health Research Institutes (NHRI), Taipei, Taiwan; °° Hôpital Necker, Paris

Genomic sequencing projects are undertaken by the

Sanger Center for NOD/Lt sequencing

Genoscope for C3H/HeJ sequencing

in collaboration

with Louis Jones, Groupe Logiciels et Banques de données, Pasteur Institute

Contacts: Philip Avner, UC Rogner
Funding: Pasteur Institute, CNRS, INSERM, JDRF, ANR, ADR, EFSD, CODDIM