A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload.
Ferritin, which is composed of H and L subunits, plays an important role in iron storage and in the control of intracellular iron distribution. Synthesis of both ferritin subunits is controlled by a common cytosolic protein, iron regulatory protein (IRP), which binds to the iron-responsive element (IRE) in the 5'-UTR of the H- and L-ferritin mRNAs. In the present study, we have identified a single point mutation (A49U) in the IRE motif of H-ferritin mRNA, in four of seven members of a Japanese family affected by dominantly inherited iron overload. Gel-shift mobility assay and Scatchard-plot analysis revealed that a mutated IRE probe had a higher binding affinity to IRP than did the wild-type probe. When mutated H subunit was overexpressed in COS-1 cells, suppression of H-subunit synthesis and of the increment of radiolabeled iron uptake were observed. These data suggest that the A49U mutation in the IRE of H-subunit is responsible for tissue iron deposition and is a novel cause of hereditary iron overload, most likely related to impairment of the ferroxidase activity generated by H subunit.
Kato
J
J
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
Fujikawa
K
K
Kanda
M
M
Fukuda
N
N
Sasaki
K
K
Takayama
T
T
Kobune
M
M
Takada
K
K
Takimoto
R
R
Hamada
H
H
Ikeda
T
T
Niitsu
Y
Y
D000368:Aged; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics* / Q000378:metabolism; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D004247:DNA; D005293:Ferritins; D007501:Iron; D002570:Ceruloplasmin