Molecular basis of new disorders of iron metabolism in man -editorial-.

I n the last few years there have been major advances in our understanding of the molecular control of cellular iron metabolism and of molecular genetics of disorders characterized by abnormal iron absorption. A fundamental step has been the cloning of HFE, the gene of HLA-related genetic hemochromatosis. 1 HFE is an atypical HLA-class I-like gene, mapping approximately 4 Megabases telomeric to HLA-A. Since the first report it was considered as a strong candidate gene for hemochromatosis, as most patients were found to be homozygous for a mis-sense mutation changing cysteine at position 282 to tyrosine (C282Y) while other patients were found to carry a second mutation that changes histidine at position 63 to aspartic acid (H63D). It is now well established that most patients with HLA-related genetic hemochromatosis are homozygous for the C282Y mutation. However, homozygosity for C282Y is found in more than 90% of North Euro-pean patients 2 but in only 64% of severely iron-loaded Italian individuals. 3 This clearly indicates that various genetic iron overload syndromes exist in addition to the HFE-related one. 4 In fact, a recent study has shown that the juvenile genetic hemo-chromatosis locus maps to chromosome 1q. 5 The spectrum of iron overload syndromes 6 is further complicated by the observation that co-inheritance of the HFE mutant allele C282Y may play an additional role in the expression of iron loading ane-mias. 7 Another fundamental step has been the recognition that the synthesis of transferrin receptor (TfR) and ferritin is regulated by cytoplasmic mRNA-binding proteins, now identified as the iron regulatory proteins (IRPs). 8,9 IRP1 and IRP2 control the expression of genes involved in iron metabolism whose transcripts contain RNA-stem-loop structures known as iron-responsive elements (IREs). Recently a new hereditary condition, characterized by the association of cataract with hyperferritinemia not related to iron overload, has been described. 10 The disorder, transmitted as an autosomal dominant condition, is due to point mutations or deletions within the IRE of the mRNA of ferritin L subunit. These mutations prevent the inhibition of ferritin synthesis which occurs when there is shortage of cellular iron. Since the severity of cataract appears to be related to the serum ferritin level, it is suggested that high ferritin levels in lens cells are responsible for cataract formation. Although the prevalence of this new condition is presently unknown, it might not be extremely rare, since until recently it was not recognized as a …