Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis.

Juvenile or type 2 hemochromatosis (JH) is transmitted as a recessive trait that leads to severe iron overload and organ damage typically before age 30 years. Linkage to a locus on chromosome 1q has been found in most patients with JH. The recently identified causal gene encodes hemojuvelin, a protein with a proposed crucial role in iron metabolism. A second, rare type of JH, with clinical expression identical to the 1q-linked form, is due to inactivation of hepcidin, the key regulator of iron homeostasis. Here we report the spectrum of mutations of the hemojuvelin gene (HJV) in 34 patients who did not show hepcidin mutations. This represents the largest cohort of patients with JH collected worldwide. We identified 17 different (16 novel) mutations of HJV, both at the homozygous and at the compound heterozygous state. Mutations either generate premature termination codons or were missense substitutions, affecting highly conserved residues, relevant to the protein structure and/or function.