Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (lan)-related gene

The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type I diabetes. Type I diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci. lddml, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of the lddml/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (lanS) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting that lan5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type I diabetes, but also in the function of the lan gene family as a whole.