Hereditary haemochromatosis: more causative genes

Abstract

Hereditary haemochromatosis (HH) is a highly prevalent iron-overload disease that is mainly associated with recessive mutations in the gene encoding HFE, a MHC class I-like protein. Interestingly, non-HFE haemochromatosis has also been reported and two other loci have been recently identified. One maps to chromosome 1q and is responsible for a juvenile form of the disease. The other, mapped to 7q22, contains the gene encoding transferrin receptor 2; a C→G transversion in this gene introduces a nonsense mutation. In addition, the genes encoding ferroportin and ferritin H are now to be added to the list. Ferroportin is a basolateral iron transporter involved in the movement of iron across the intestinal enterocytes to the bloodstream. Linkage analysis in a large Dutch family with inherited iron overload led to the identification of a single A→C transversion at position 734 (Ref. 1). This mutation substitutes an uncharged Asn residue at position 144, located within one of the predicted transmembrane domains of the protein, with a charged His residue. The expected reduction in the hydrophobicity of this domain could affect the folding of the molecule. Ferritin H is an iron-storage protein whose expression is essentially controlled at the translational level via the association of a protein trans-regulator with a cis-regulatory RNA element in the mRNA leader. A single mutation in this RNA structure has been found in a Japanese family 2. Strikingly, this mutation seems to increase the affinity of the RNA motif for the protein trans-regulator, resulting in reduced translation of the mutant mRNA.