The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1
The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1
复制标题
DOI：
10.2337/diabetes.51.6.1972
复制
发表时间：
2002-06-01
期刊：
影响因子：
7.7
通讯作者：
Markholst, H
中科院分区：
文献类型：
--
作者：
Hornum, L;Romer, J;Markholst, H
易患糖尿病 (DP) BB 大鼠会自发发展为类似于人类 1 型糖尿病的胰岛素依赖性糖尿病。他们还表现出终生 T 细胞淋巴细胞减少症。功能和遗传数据支持这样的假设：导致淋巴细胞减少的基因 Lyp 也是一种糖尿病易感基因，名为 Iddm1。我们构建了该区域的 550 kb P1 衍生人工染色体重叠群。在这里，我们提出了一个校正后的遗传图谱，将遗传间隔减少到 0.2 cM，物理间隔减少到 150-290 kb。共有 13 个基因和 6 个 GenomeScan 模型被分配给 HSA7q36.1 上的同源人类 DNA 片段，其中 8 个属于免疫相关核苷酸家族（Ian 基因）。其中两个与小鼠 Ian1 和 -4 是直系同源的，它们都是 Iddm1 的优秀候选者。在正常大鼠中，它们在胸腺和脾脏的 T 细胞区域表达。在淋巴细胞减少的大鼠胸腺中，Ian1 表现出野生型表达模式，而 Ian4 表达减少。其编码序列的突变筛选揭示了淋巴细胞减少大鼠中 Ian4 的移码突变。该突变产生截短的蛋白质，其中 COOH 末端的 215 个氨基酸（包括将蛋白质定位到线粒体外膜的锚）被 19 个其他氨基酸取代。我们认为 Ian4 与 Iddm1 相同。
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.