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


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=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.
Nagayoshi
Yasuhiro
Y
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan. ynagayos@kumamoto-u.ac.jp
Nakayama
Masafumi
M
Suzuki
Satoru
S
Hokamaki
Jun
J
Shimomura
Hideki
H
Tsujita
Kenichi
K
Fukuda
Masaya
M
Yamashita
Takuro
T
Nakamura
Yoshinori
Y
Sugiyama
Seigo
S
Ogawa
Hisao
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D009202:Cardiomyopathies / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D018389:Codon, Nonsense; D005260:Female; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000150:complications* / Q000453:epidemiology / Q000235:genetics; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D055815:Young Adult
D023181:Antimicrobial Cationic Peptides; D018389:Codon, Nonsense; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins