Hemochromatosis Modifier Genes

描述（由申请人提供）：单一突变（HFE C282 Y）的纯合性是绝大多数血色素沉着症病例的原因，但纯合子的表型表达差异很大。在本申请中待检验的假设是修饰基因负责表型变异性。为了验证这一假设，我们提出了两个具体目标。 具体目标1：利用小鼠染色体置换株（CSS）鉴定影响铁表型的染色体。铁代谢在近交系小鼠中以品系特异性方式变化。我们已经确定A/J品系的小鼠具有“高铁”表型。它们吸收的铁是C57 BL/6 J小鼠吸收的铁的两倍，并且还在肝脏中存款更多的新吸收的铁，具有更高的转铁蛋白饱和度，更高的肝脏铁含量，并且将更多的铁从巨噬细胞转移到肝细胞。我们将利用的CSS是在C57 BL/6 J背景上的，但是每个菌株对于从A/J捐赠的一条染色体（1-19，X，Y）是纯合的。其中铁表型不同于C57 BL/6 J的CSS菌株将立即鉴定含有修饰基因的染色体。感兴趣的CSS将与Hfe突变C57 BL/6 J小鼠杂交，以确定所鉴定的染色体修饰Hfe表型。特定目标2：通过缩小特定目标1中鉴定的染色体上的感兴趣区域来鉴定候选修饰基因。从C57 BL/6 J和A/J菌株中产生了重组同源菌株（RCS）。将对特定目标1中鉴定的含有染色体片段的RCS进行表型分析，以缩小候选修饰子区域。定位于候选区域的基因将被认为是修饰铁表型并因此影响血色病表达的基因的候选者。

DESCRIPTION (provided by applicant): Homozygosity for a single mutation (HFE C282Y) is responsible for the vast majority of cases of hemochromatosis, yet phenotypic expression in homozygotes varies widely. The hypothesis to be tested in this application is that modifier genes are responsible for the phenotypic variability. To test this hypothesis, we propose two specific aims. Specific Aim 1: Utilize murine chromosome substitution strains (CSSs) to identify chromosomes that influence the iron phenotype. Iron metabolism in inbred mice varies in a strain-specific manner. We have established that mice of the A/J strain have a "high iron" phenotype. They absorb twice the amount of iron than C57BL/6J mice absorb and also deposit more newly absorbed iron in the liver, have higher transferrin saturation, higher liver iron content and transfer more iron from macrophages to hepatocytes. The CSSs we will utilize are on a C57BL/6J background, but each strain is homozygous for one chromosome (1-19, X,Y) donated from A/J. A CSS strain in which the iron phenotype differs from C57BL/6J will immediately identify a chromosome containing a modifier gene(s). CSSs of interest will be crossed with Hfe mutant C57BL/6J mice to establish that the chromosome identified modifies the Hfe phenotype. Specific Aim 2: Identify candidate modifier genes by narrowing the regions of interest on the chromosomes identified in Specific Aim1. Recombinant congenic strains (RCS) have been generated from the C57BL/6J an A/J strains. RCS containing segments of chromosomes identified in Specific Aim 1 will be phenotyped to narrow the candidate modifier region. Genes localized to the candidate region will be considered candidates for genes that modify the iron phenotype and hence affect expression of hemochromatosis.