Non-HFE haemochromatosis

Abstract

Non-HFE hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFE gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism.

Figure 1

Structure of human hemojuvelin and positions of mutations. A: The exon structure of human hemojuvelin is shown with positions of known mutations marked[6,13-24,30,39]. *Q6H was found associated with C321X; B: Predicted structure of the full length HJV protein, showing the positions of structural domains and motifs. SP, signal peptide; PG, poly-glycine sequence; RGD, RGD motif; PP, poly-proline sequence; vWF, partial von Willebrand factor type D domain; N, potential N-linked glycosylation sites; GPI, GPI-attachment site; TM, transmembrane domain, cleaved after GPI attachment.

Figure 2

Structure of human hepcidin and positions of mutations. A: The exon structure of human hepcidin is shown with positions of known mutations marked[5,29-37]. B: Predicted structure of the hepcidin peptide. SP, signal peptide; Pro, pro-region; Mature, 25 amino acid mature hepcidin peptide.

Figure 3

Structure of human transferrin receptor 2 (TfR2) and positions of mutations. A: The exon structure of human TfR2 is shown with positions of known mutations marked[7,30,40-52]. The frameshift mutations R30fsX60 and P555fsX561 are also known as E60X and V561X respectively. G792R may be associated with R396X; B: Predicted structure of TfR2 protein. YQRV, endocytosis signal; TM, transmembrane domain; RGD, RGD motif; S, predicted interchain disulphide bonds; N, potential N-linked glycosylation sites.

Figure 4

Structure of human ferroportin and positions of mutations. A: The exon structure of human ferroportin is shown with positions of known mutations marked[8,9,60-85]. IRE, iron response element; B: Predicted structure of ferroportin protein. Predicted transmembrane domains are shaded; N, potential N-linked glycosylation sites.