Le Gall J Y, David V, Yaouanq J, Périchon M, Blayau M, Jouanolle A M, Mauvieux V, el Kahloun A, Chauvel B, Dorval I
Laboratoire de Biochimie Médicale B. Faculté de Médecine, Rennes.
Bull Acad Natl Med. 1993 Feb;177(2):187-98; discussion 199-201.
Haemochromatosis is an inherited disorder of iron metabolism characterized by a general iron over loading. Without diagnosis and early treatment, it is a serious and potentially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estimated at 0.06 in Brittany, so that haemochromatosis may be the most common genetic disease in this area. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption through duodenal mucosa is excessive. However we don't know if it is a primary event. The gene is also unknown but in 1975 it was located on the short arm of chromosome 6, closely linked to the HLA class I region, less than 1 cM from HLA-A. None of the genes coding for the known iron proteins could be the haemochromatosis gene because of their chromosomal localization. In order to locate this gene with precision, we have used a reverse genetic approach now called positional cloning. Characterization of new polymorphic markers and linkage disequilibrium analysis, have led us to locate the gene within a 350 kb region around HLA-A. We have then searched for all the structural genes in this region. Seven new genes have been so identified and located with precision. A structural analysis of these genes was undertaken to find an eventual abnormality in patients.
血色素沉着症是一种遗传性铁代谢紊乱疾病，其特征是全身铁过载。如果不进行诊断和早期治疗，它是一种严重的、可能致命的疾病，尤其是会导致心力衰竭或肝细胞癌。据估计，布列塔尼地区的基因患病率为0.06，因此血色素沉着症可能是该地区最常见的遗传疾病。该疾病的生化缺陷尚不清楚；只有一个事实是明确的：十二指肠黏膜对铁的吸收过多。然而，我们不知道这是否是一个原发性事件。致病基因也未知，但在1975年它被定位在6号染色体的短臂上，与HLA I类区域紧密连锁，距离HLA - A不到1厘摩。由于已知铁蛋白的编码基因的染色体定位，它们都不可能是血色素沉着症基因。为了精确地定位这个基因，我们采用了一种现在称为定位克隆的反向遗传学方法。新的多态性标记的表征和连锁不平衡分析，使我们将该基因定位在HLA - A周围350 kb的区域内。然后我们在这个区域搜索了所有的结构基因。这样就精确地鉴定并定位了7个新基因。对这些基因进行了结构分析，以寻找患者中可能存在的异常情况。
