A Q312X mutation in the hemojuvelin gene is associated with cardiomyopathy due to juvenile haemochromatosis ☆

Background and aims: Juvenile haemochromatosis (JH) is an autosomal recessive iron disorder characterized by the early onset of secondary cardiomyopathy. The candidate modifier genes are hemojuvelin ( HJV ) and hepcidin antimicrobial peptide ( HAMP ). In the Japanese population, the prevalence of JH is quite low. The influence of HJV mutation on the JH phenotype is still unclear. Methods and results: We searched for possible mutations in a Japanese family with 2 members who were JH patients with severe heart failure. To search for possible variants in the HJV and HAMP genes, we performed direct sequencing in the family members. A homozygous nonsense mutation in exon 4 of HJV (Q312X) was identified in the JH patients and their mother. Three individuals in the family were heterozygous for this mutation. Subsequently, we evaluated the frequency of Q312X mutation in a large population ( n w=361) without heart failure, using allele‐specific real‐time PCR assay. No Q312X mutation was detected in this population. In the patients with the homozygous HJV mutation, iron loading revealed high serum ferritin concentration with accompanying elevated transferrin iron saturation. In contrast, ferritin levels were within the normal range in individuals with the heterozygous mutation. Conclusions: We found a nonsense mutation in the HJV gene. This mutation elevates ferritin levels and leads to JH associated with severe cardiomyopathy.