The Diabetes-Prone BB Rat Carries a Frameshift Mutation in Ian4, a Positional Candidate of Iddm1
- 1Type I Pharmacology, Hagedorn Research Institute, Gentofte, Denmark
- 2Pharmacological Research 4, Novo Nordisk, Bagsværd, Denmark
Diabetes-prone (DP) BB rats spontaneously develop insulin-dependent diabetes resembling human type 1 diabetes. They also exhibit lifelong T-cell lymphopenia. Functional and genetic data support the hypothesis that the gene responsible for the lymphopenia, Lyp, is also a diabetes susceptibility gene, named Iddm1. We constructed a 550-kb P1-derived artificial chromosome contig of the region. Here, we present a corrected genetic map reducing the genetic interval to 0.2 cM and the physical interval to 150–290 kb. A total of 13 genes and six GenomeScan models are assigned to the homologous human DNA segment on HSA7q36.1, 8 of which belong to the family of immune-associated nucleotides (Ian genes). Two of these are orthologous to mouse Ian1 and -4, both excellent candidates for Iddm1. In normal rats, they are expressed in the thymus and T-cell regions of the spleen. In the thymus of lymphopenic rats, Ian1 exhibits wild-type expression patterns, whereas Ian4 expression is reduced. Mutational screening of their coding sequences revealed a frameshift mutation in Ian4 among lymphopenic rats. The mutation results in a truncated protein in which the COOH-terminal 215 amino acids—including the anchor localizing the protein to the outer mitochondrial membrane—are replaced by 19 other amino acids. We propose that Ian4 is identical to Iddm1.
Address correspondence and reprint requests to Helle Markholst, MD, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. E-mail:.
Received for publication 21 December 2001 and accepted in revised form 21 February 2001.
The Hagedorn Research Institute is an independent basic research component of Novo Nordisk. H.M. and L.H. are employees of Novo Nordisk.
DP, diabetes-prone; DR, diabetes-resistant; PAC, P1-derived artificial chromosome.