Sheng Jian Rong, Jagodic Maja, Dahlman Ingrid, Becanovic Kristina, Nohra Rita, Marta Monica, Iacobaeus Ellen, Olsson Tomas, Wallström Erik
Center for Molecular Medicine, Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
Genetics. 2005 May;170(1):283-9. doi: 10.1534/genetics.104.035261. Epub 2005 Feb 16.
Multiple sclerosis (MS) and its animal model, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), share a complex genetic predisposition with contributions from the major histocompatibility complex class II genes and many other genes. Linkage mapping in F(2) crosses between the susceptible DA rat strain and the resistant ACI or BN rat strains in various models of autoimmune neuroinflammation have repeatedly displayed suggestive linkage to a region on rat chromosome 15. A direct study of this region was undertaken in congenic strains by transferring resistant ACI alleles to the susceptible DA background. Phenotypic analysis demonstrated lower maximal and cumulative EAE scores in the DA.ACI-D15Rat6-D15Rat71 (C15), DA.ACI-D15Rat6-D15Rat48, D15Rat126-D15Rat71 (C15R3b), and DA.ACI-D15Rat23-D15rat71 (C15R4) strains compared to the parental DA rat strain. Linkage analysis was then performed in a (DA x PVG.AV1)F(7) advanced intercross line, resulting in a LOD score of 4.7 for the maximal EAE score phenotype at the peak marker D15Rat71 and a confidence interval of 13 Mb, overlapping with the congenic fragment defined by the C15R3b and the C15R4 strains. Thus, a new MOG-EAE locus with the designation Eae19 is identified on rat chromosome 15. There are 32 confirmed or predicted genes in the confidence interval, including immune-responsive gene 1 and neuronal ceroid lipofuscinose gene 5. Definition of loci such as Eae19 enables the characterization of genetically regulated, evolutionary conserved disease pathways in complex neuroinflammatory diseases.
多发性硬化症（MS）及其动物模型，髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎（MOG-EAE），具有复杂的遗传易感性，主要组织相容性复合体II类基因和许多其他基因都对此有影响。在各种自身免疫性神经炎症模型中，易感的DA大鼠品系与抗性的ACI或BN大鼠品系之间的F(2)杂交的连锁图谱反复显示与大鼠15号染色体上的一个区域存在暗示性连锁。通过将抗性ACI等位基因转移到易感的DA背景中，在同源品系中对该区域进行了直接研究。表型分析表明，与亲代DA大鼠品系相比，DA.ACI-D15Rat6-D15Rat71（C15）、DA.ACI-D15Rat6-D15Rat48、D15Rat126-D15Rat71（C15R3b）和DA.ACI-D15Rat23-D15rat71（C15R4）品系的最大和累积EAE评分较低。然后在（DA×PVG.AV1）F(7)高级杂交系中进行连锁分析，在峰值标记D15Rat71处，最大EAE评分表型的LOD得分为4.7，置信区间为13 Mb，与C15R3b和C15R4品系定义的同源片段重叠。因此，在大鼠15号染色体上鉴定出一个新的MOG-EAE基因座，命名为Eae19。在置信区间内有32个已确认或预测的基因，包括免疫反应基因1和神经元蜡样脂褐质沉积症基因5。定义诸如Eae19这样的基因座能够表征复杂神经炎症性疾病中遗传调控、进化保守的疾病途径。
