The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1.
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.
Hornum
Lars
L
Type I Pharmacology, Hagedorn Research Institute, Gentofte, Denmark.
Rømer
John
J
Markholst
Helle
H
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D016368:Frameshift Mutation; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D051381:Rats; D011913:Rats, Inbred BB; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment
C485688:GIMAP4 protein, human; C425002:Ian4 protein, mouse; D008565:Membrane Proteins; D019204:GTP-Binding Proteins; C522727:Gimap4 protein, rat