Vercesi E, Cerani P, Rolandi V, Rovati A, Bergamaschi G
Department of Internal Medicine and Medical Therapy, Section of Internal Medicine and Medical Oncology, University of Pavia Medical School and IRCCS Policlinico S. Matteo, Pavia, Italy.
Haematologica. 2000 Aug;85(8):787-91.
Hereditary hemochromatosis (HHC) is a common, recessively inherited, genetic disorder associated with an abnormality of the HFE gene. Subjects homozygous for a point mutation in the gene coding sequence, leading to the amino acid substitution C282Y, are usually affected by the disease. A second point mutation, causing the amino acid substitution H63D, has been described, and compound heterozygotes for the two mutations or homozygotes for the H63D mutation are at risk of developing a milder form of HHC. In populations of northern European origin the C282Y substitution accounts for more than 90% of cases of HHC. In Italy, however, fewer than 70% of patients with HHC are homozygous or compound heterozygous for HFE mutations. Even in the absence of mutations in its coding region, the HFE gene might be involved in the pathogenesis of HHC through inhibition of transcription of the gene or reduced stability of its mRNA.
Since little is known about the regulation of HFE expression, we investigated 17 subjects heterozygous for one of the HFE mutations and with biochemical evidence of iron overload and compared the levels of wild type and mutated mRNAs in their peripheral blood cells. c-DNA regions flanking the mutated codons were amplified by reverse transcriptase polymerase chain reaction (PCR). PCR products derived from the two alleles were differentiated and quantified by digestion with restriction enzymes, electrophoresis in an agarose gel stained with ethidium bromide and densitometric scanning of the gel.
In all cases wild type and mutated mRNAs were expressed at similar levels, suggesting that reduced expression of an HFE allele coding a normal protein is not involved in the pathogenesis of iron overload. However, we can not rule out that a tissue specific regulation of HFE expression in the cells directly involved in iron absorption is altered and contributes to the pathogenesis of the disease. E INTERPRETATION AND CONCLUSIONS: Our results suggest that primary iron overload is a multigenic syndrome; this hypothesis is strongly supported by the recent demonstration that the juvenile hemochromatosis locus maps to human chromosome 1q.
遗传性血色素沉着症（HHC）是一种常见的隐性遗传基因疾病，与HFE基因异常有关。编码序列中存在导致氨基酸替换C282Y的点突变的纯合子个体通常会患此病。已发现另一种导致氨基酸替换H63D的点突变，这两种突变的复合杂合子或H63D突变的纯合子有患症状较轻的HHC的风险。在北欧血统人群中，C282Y替换占HHC病例的90%以上。然而，在意大利，HHC患者中不到70%是HFE突变的纯合子或复合杂合子。即使其编码区没有突变，HFE基因也可能通过抑制该基因的转录或降低其mRNA的稳定性而参与HHC的发病机制。
由于对HFE表达调控了解甚少，我们研究了17名携带一种HFE突变且有铁过载生化证据的杂合子个体，并比较了他们外周血细胞中野生型和突变型mRNA的水平。通过逆转录聚合酶链反应（PCR）扩增突变密码子两侧的cDNA区域。用限制性酶消化、在溴化乙锭染色的琼脂糖凝胶中电泳以及对凝胶进行光密度扫描，对来自两个等位基因的PCR产物进行区分和定量。
在所有病例中，野生型和突变型mRNA的表达水平相似，这表明编码正常蛋白质的HFE等位基因表达降低与铁过载的发病机制无关。然而，我们不能排除直接参与铁吸收的细胞中HFE表达的组织特异性调控发生改变并促成该疾病发病机制的可能性。
我们的结果表明，原发性铁过载是一种多基因综合征；这一假说得到了最近一项研究结果的有力支持，该研究表明青少年血色素沉着症基因座定位于人类1号染色体。
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