Modifiers of Iron Loading in Mice

描述(申请人提供)：血色沉着症的特征是肠道铁吸收的慢性增加，导致肝脏、心脏、胰腺和其他器官中铁的过度沉积。HFE基因突变纯合子或FPN基因突变杂合子的患者有发生这些并发症的风险，但疾病严重程度存在差异。对HFE血色沉着症的研究尤其充分；一些人在生命的第三个十年有严重的并发症，而另一些人到老年时很少或根本没有铁毒性的证据。疾病的严重程度与组织铁负荷的程度有关。这项提议的目标是确定改变铁负载表型的基因。这将用小鼠来完成，因为小鼠的铁代谢与人类相似，实验室里也有HFE血色病和FPN血色病的小鼠模型。初步研究表明，C57BL/10和SWR两个近交系小鼠在组织铁负荷表型上存在显著差异。C57BL/10小鼠在肝脏和脾组织中积累的铁很少，而SWR小鼠在这两个组织中积累了大量的铁负荷。在数量性状基因座(QTL)分析中使用了定量的肝和脾铁负荷数据，以确定具有高概率解释两个菌株之间铁负荷差异的染色体区域。在对96只来自这些品系杂交的回交动物的分析中，至少检测到4个与肝脏铁负荷有关的QTL(LOD得分2.9~4.0)，1个与脾铁负荷有关的QTL(LOD 8.3)。这项建议描述的目的是(1)确定负责这些QTL的基因，以及(2)确定这些和其他潜在的铁负荷修饰物是否也改变了HFE和FPN血色素沉着症小鼠的表型。

DESCRIPTION (provided by applicant): Hemochromatosis is characterized by a chronic increase in intestinal iron absorption, leading to excessive iron deposition in the liver, heart, pancreas and other organs. Patients who are homozygous for mutations in the HFE gene or heterozygous for mutations in the FPN gene are at risk for these complications, but there is variability in disease severity. This has been particularly well studied for HFE hemochromatosis; some individuals have severe complications in the third decade of life, whereas others reach old age with little or no evidence of iron toxicity. The severity of the disease correlates with the extent of tissue iron loading. The goal of this proposal is to identify genes that modify iron-loading phenotypes. This will be done using mice, because mice are similar to humans in their iron metabolism, and mouse models of both HFE hemochromatosis and FPN hemochromatosis are available in the laboratory. Preliminary studies show that two inbred mouse strains, C57BL/10 and SWR, differ markedly in their tissue iron loading phenotypes. C57BL/10 mice accumulate little iron in the liver and spleen, while SWR mice accumulate large iron burdens in both tissues. Quantitative liver and spleen iron loading data were used in a quantitative trait locus (QTL) analysis to identify chromosomal regions that have a high probability of accounting for differences in iron loading between the two strains. In the analysis of 96 N2 backcross animals from a cross between these strains, at least 4 QTLs (LOD scores 2.9 - 4.0) were identified for liver iron loading, and one QTL (LOD 8.3) was identified for spleen iron loading. The aims described in this proposal are (1) to identify the genes responsible for these QTLs, and (2) to determine whether these and other potential modifiers of iron loading also modify the phenotypes of mice with Hfe and Fpn hemochromatosis.