A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.

Hdl Handle:
http://hdl.handle.net/10147/200338
Title:
A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.
Authors:
Cao, Wei; McMahon, Mary; Wang, Bo; O'Connor, Rosemary; Clarkson, Michael
Affiliation:
Cell Biology Laboratory, Department of Biochemistry, University College Cork, Cork, Ireland. caowei_111@yahoo.com.cn
Citation:
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:
Elsevier
Journal:
Blood cells, molecules & diseases
Issue Date:
15-Jan-2010
URI:
http://hdl.handle.net/10147/200338
DOI:
10.1016/j.bcmd.2009.09.003
PubMed ID:
19800271
Abstract:
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:
Article
Language:
en
Description:
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.
MeSH:
Cataract; Cell 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
ISSN:
1096-0961

Full metadata record

DC FieldValue Language
dc.contributor.authorCao, Weien
dc.contributor.authorMcMahon, Maryen
dc.contributor.authorWang, Boen
dc.contributor.authorO'Connor, Rosemaryen
dc.contributor.authorClarkson, Michaelen
dc.date.accessioned2012-01-05T15:59:59Z-
dc.date.available2012-01-05T15:59:59Z-
dc.date.issued2010-01-15-
dc.identifier.citationA 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.en
dc.identifier.issn1096-0961-
dc.identifier.pmid19800271-
dc.identifier.doi10.1016/j.bcmd.2009.09.003-
dc.identifier.urihttp://hdl.handle.net/10147/200338-
dc.descriptionThe 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.en
dc.description.abstractThe 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.-
dc.language.isoenen
dc.publisherElsevieren
dc.subject.meshCataract-
dc.subject.meshCell Line-
dc.subject.meshDNA Mutational Analysis-
dc.subject.meshDown-Regulation-
dc.subject.meshFeedback, Physiological-
dc.subject.meshFemale-
dc.subject.meshFerritins-
dc.subject.meshHeterozygote-
dc.subject.meshHumans-
dc.subject.meshImmunoglobulin Fc Fragments-
dc.subject.meshImmunoglobulin G-
dc.subject.meshIron-
dc.subject.meshIron Regulatory Protein 1-
dc.subject.meshIron Regulatory Protein 2-
dc.subject.meshMiddle Aged-
dc.subject.meshModels, Molecular-
dc.subject.meshPedigree-
dc.subject.meshPoint Mutation-
dc.subject.meshRNA, Messenger-
dc.subject.meshRNA-Binding Proteins-
dc.subject.meshRecombinant Fusion Proteins-
dc.subject.meshResponse Elements-
dc.subject.meshSyndrome-
dc.titleA case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.en
dc.typeArticleen
dc.contributor.departmentCell Biology Laboratory, Department of Biochemistry, University College Cork, Cork, Ireland. caowei_111@yahoo.com.cnen
dc.identifier.journalBlood cells, molecules & diseasesen
dc.description.provinceMunster-

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