MacMurray Armand J, Moralejo Daniel H, Kwitek Anne E, Rutledge Elizabeth A, Van Yserloo Brian, Gohlke Paul, Speros Sara J, Snyder Ben, Schaefer Jonathan, Bieg Sabine, Jiang Jianjie, Ettinger Ruth A, Fuller Jessica, Daniels Terri L, Pettersson Anna, Orlebeke Kimberly, Birren Bruce, Jacob Howard J, Lander Eric S, Lernmark Ake
Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Genome Res. 2002 Jul;12(7):1029-39. doi: 10.1101/gr.412702.
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 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci. Iddm1, 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 Iddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) 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 Ian5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.
BB（BioBreeding）大鼠是自发性自身免疫性糖尿病的最佳模型之一，用于研究与1型糖尿病相关的非主要组织相容性复合体（MHC）基因座。糖尿病易感BB（BBDP）大鼠的1型糖尿病是多基因的，取决于多个基因座的突变。位于4号染色体上的Iddm1负责淋巴细胞减少（lyp）表型，对糖尿病的发生至关重要。在本研究中，我们报告了Iddm1/lyp基因座的定位克隆。我们发现淋巴细胞减少是由于免疫相关核苷酸（IAN）相关基因家族的一个新成员（Ian5）发生移码缺失，导致该蛋白质的很大一部分被截短。在其他37个非淋巴细胞减少且非糖尿病的近交系大鼠品系中未发现这种突变。IAN基因家族紧密聚集在大鼠4号染色体、小鼠6号染色体和人类7号染色体上，其特征了解甚少。该家族的一些成员已被证明在成熟T细胞中表达，并在胸腺T细胞发育过程中开启，这表明Ian5可能是T细胞发育的关键因素。因此，淋巴细胞减少突变不仅可能有助于阐明1型糖尿病，还可能有助于了解整个Ian基因家族的功能。
