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Gene Review:

Iddm1 - Insulin dependent diabetes mellitus QTL 1

Rattus norvegicus

Klöting, I. et al., Yokoi, N., Klöting, I. et al., Yokoi, N. et al., Klöting, I. et al., et al.

Klöting, van den Brandt, Klöting, Radović, Klöting, van den Brandt, Kuttler, Klöting, Klöting,

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Disease relevance of Iddm1

Iddm1 in the rat causes peripheral T cell lymphopenia, which is associated with a dramatically shortened peripheral T cell life span [1].

High impact information on Iddm1

The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes in which the major susceptibility locus Iddm/kdp1 accounts, in combination with MHC, for most of the genetic predisposition to diabetes [2].
The analysis of three crosses has led to the revelation of a major IDDM susceptibility gene, termed Iddm/kdp1, on rat chromosome (Chr) 11 [3].
Several crossing studies have demonstrated that beside the class II genes of the major histocompatibility complex (MHC, Iddm1) additional non-MHC genes are involved in diabetes development [4].
About 50% of Iddm1 and Iddm2 homozygous first backcross hybrids (BC1) usually develop diabetes [5].
In this paper, I review our positional cloning analysis of Iddm/kdp1 and propose a two-gene model of the development of type 1 diabetes in which two major susceptibility genes, Cblb and MHC, determine autoimmune reaction and tissue specificity to pancreatic beta-cells, respectively [6].

Biological context of Iddm1

All hybrids were used in a genome-wide scan carried out with 238 microsatellite markers covering about 92% of the genome.Significantly more Iddm1 and Iddm2 homozygous BC1 hybrids became diabetic (69 vs. 50%, p<0.003) with an age at onset of 91+/-31 days [5].
Several crossing studies with diabetic BB rats have shown that in addition to the lymphopenia (Iddm1) and the MHC class II genes of the RT1U haplotype (Iddm2) there are further non-MHC genes essential for diabetes development [7].

Other interactions of Iddm1

It is supposed that diabetes protective genes of SHR must be located on both chromosomal segments and that these suppress the action of the essential and most important genes of diabetes development in the BB/OK rat, Iddm1, and Iddm2 [8].

References

A diabetogenic gene prevents T cells from receiving costimulatory signals. Moore, J.K., Gold, D.P., Dreskin, S.C., Lernmark, A., Bellgrau, D. Cell. Immunol. (1999) [Pubmed]
Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Yokoi, N., Komeda, K., Wang, H.Y., Yano, H., Kitada, K., Saitoh, Y., Seino, Y., Yasuda, K., Serikawa, T., Seino, S. Nat. Genet. (2002) [Pubmed]
A non-MHC locus essential for autoimmune type I diabetes in the Komeda Diabetes-Prone rat. Yokoi, N., Kanazawa, M., Kitada, K., Tanaka, A., Kanazawa, Y., Suda, S., Ito, H., Serikawa, T., Komeda, K. J. Clin. Invest. (1997) [Pubmed]
Genetic variation in the multifunctional transcription factor Yy1 and type 1 diabetes mellitus in the BB rat. Klöting, N., Klöting, I. Mol. Genet. Metab. (2004) [Pubmed]
Alleles of diabetes-resistant BN rats contribute to insulin-dependent type 1 diabetes mellitus. Klöting, I., van den Brandt, J., Klöting, N., Radović, B. J. Autoimmun. (2003) [Pubmed]
Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat. Yokoi, N. Exp. Anim. (2005) [Pubmed]
Crosses between diabetic BB/OK and wild rats confirm that a third gene is essential for diabetes development. Klöting, I., Kovacs, P. Acta diabetologica. (1998) [Pubmed]
Genes of SHR rats protect spontaneously diabetic BB/OK rats from diabetes: lessons from congenic BB.SHR rat strains. Klöting, I., van den Brandt, J., Kuttler, B. Biochem. Biophys. Res. Commun. (2001) [Pubmed]

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