A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.
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Affiliation
Cell Biology Laboratory, Department of Biochemistry, University College Cork, Cork, Ireland. caowei_111@yahoo.com.cnIssue Date
2010-01-15MeSH
CataractCell Line
DNA Mutational Analysis
Down-Regulation
Feedback, Physiological
Female
Ferritins
Heterozygote
Humans
Immunoglobulin Fc Fragments
Immunoglobulin G
Iron
Iron Regulatory Protein 1
Iron Regulatory Protein 2
Middle Aged
Models, Molecular
Pedigree
Point Mutation
RNA, Messenger
RNA-Binding Proteins
Recombinant Fusion Proteins
Response Elements
Syndrome
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A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome. 2010, 44 (1):22-7 Blood Cells Mol. Dis.Publisher
ElsevierJournal
Blood cells, molecules & diseasesDOI
10.1016/j.bcmd.2009.09.003PubMed ID
19800271Abstract
The hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by juvenile-onset cataracts and elevated serum ferritin levels. It is caused by mutation in the iron response element (IRE) within the 5'UTR of L-ferritin gene. The mutation results in a loss of post-transcriptional negative feedback exerted by the interaction between iron regulatory proteins 1, 2 (IRP1 and IRP2) and IRE, which leads to uncontrolled expression of L-ferritin. In this paper, we describe the molecular pathogenesis of non-hereditary hyperferritinemia cataract syndrome (non-H-HCS) in a patient with typical HHCS ocular lens morphology and high ferritin levels without obvious family history. Initial sequencing of the full-length L-ferritin cloned from genomic DNA demonstrated a mutation (C33>T) in the IRE of the affected patient but not in her unaffected family members. The mutation (C/T heterozygote) was also detected in cDNA derived from her blood mononuclear cells. Structure-prediction-modeling indicates that this mutation would significantly alter the secondary structure of the IRE, resulting in a loss of the interaction between IRP and IRE. By using IRP1/IRP2-human IgG1 Fc fusion proteins, we established a novel in vitro report system (modified ELISA) to verify impaired IRE/IRP binding. Both the C33>U and A40G mutations (the first identified mutation for HHCS) showed a dramatically decreased binding to IRP1/IRP2 protein, compared to the normal IRE RNA. Surprisingly, a decrease in L-ferritin mRNA levels was observed in the affected patient compared to controls suggesting a mechanism of transcriptional negative feedback by high intracellular L-ferritin protein levels not described heretofore. Taken together, spontaneous mutation in the IRE of L-ferritin may cause non-H-HCS by the same mechanism as HHCS. In addition, under abnormal circumstances, the protein level of L-ferritin may be principally controlled by post-transcriptional regulation rather than the transcriptional regulation. The successful establishment of an ELISA report system provides an alternative method to evaluate precisely the interaction between protein and RNA.Item Type
ArticleLanguage
enISSN
1096-0961ae974a485f413a2113503eed53cd6c53
10.1016/j.bcmd.2009.09.003
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