Mutations in the HFE2 gene cause iron overload in chromosome 1q-linked juvenile hemochromatosis. This study identifies HFE2 as the gene responsible for this condition, which is an autosomal recessive disorder characterized by early-onset iron overload leading to cardiomyopathy, diabetes, and hypogonadism. The HFE2 gene, named hemojuvelin, is located on chromosome 1q and is involved in iron metabolism. The study found that mutations in HFE2, particularly the G320V substitution, are associated with juvenile hemochromatosis. HFE2 expression is restricted to liver, heart, and skeletal muscle, similar to hepcidin, a key protein in iron metabolism. However, hemojuvelin is not the hepcidin receptor, but rather modulates hepcidin expression. The study also found that mutations in HFE2 lead to reduced hepcidin levels despite iron overload, suggesting that HFE2 acts as a modulator of hepcidin expression. The study also found that juvenile hemochromatosis and adult-onset hereditary hemochromatosis are on the same biochemical and phenotypic spectrum, with juvenile hemochromatosis representing the more severe, earlier-onset phenotype with absent or very low hepcidin. The identification of HFE2 provides new therapeutic and diagnostic opportunities for the management of iron-related disorders.Mutations in the HFE2 gene cause iron overload in chromosome 1q-linked juvenile hemochromatosis. This study identifies HFE2 as the gene responsible for this condition, which is an autosomal recessive disorder characterized by early-onset iron overload leading to cardiomyopathy, diabetes, and hypogonadism. The HFE2 gene, named hemojuvelin, is located on chromosome 1q and is involved in iron metabolism. The study found that mutations in HFE2, particularly the G320V substitution, are associated with juvenile hemochromatosis. HFE2 expression is restricted to liver, heart, and skeletal muscle, similar to hepcidin, a key protein in iron metabolism. However, hemojuvelin is not the hepcidin receptor, but rather modulates hepcidin expression. The study also found that mutations in HFE2 lead to reduced hepcidin levels despite iron overload, suggesting that HFE2 acts as a modulator of hepcidin expression. The study also found that juvenile hemochromatosis and adult-onset hereditary hemochromatosis are on the same biochemical and phenotypic spectrum, with juvenile hemochromatosis representing the more severe, earlier-onset phenotype with absent or very low hepcidin. The identification of HFE2 provides new therapeutic and diagnostic opportunities for the management of iron-related disorders.