A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.
dc.contributor.author | Cao, Wei | |
dc.contributor.author | McMahon, Mary | |
dc.contributor.author | Wang, Bo | |
dc.contributor.author | O'Connor, Rosemary | |
dc.contributor.author | Clarkson, Michael | |
dc.date.accessioned | 2012-01-05T15:59:59Z | |
dc.date.available | 2012-01-05T15:59:59Z | |
dc.date.issued | 2010-01-15 | |
dc.identifier.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. | en |
dc.identifier.issn | 1096-0961 | |
dc.identifier.pmid | 19800271 | |
dc.identifier.doi | 10.1016/j.bcmd.2009.09.003 | |
dc.identifier.uri | http://hdl.handle.net/10147/200338 | |
dc.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. | en |
dc.description.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. | |
dc.language.iso | en | en |
dc.publisher | Elsevier | en |
dc.subject.mesh | Cataract | |
dc.subject.mesh | Cell Line | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Down-Regulation | |
dc.subject.mesh | Feedback, Physiological | |
dc.subject.mesh | Female | |
dc.subject.mesh | Ferritins | |
dc.subject.mesh | Heterozygote | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Immunoglobulin Fc Fragments | |
dc.subject.mesh | Immunoglobulin G | |
dc.subject.mesh | Iron | |
dc.subject.mesh | Iron Regulatory Protein 1 | |
dc.subject.mesh | Iron Regulatory Protein 2 | |
dc.subject.mesh | Middle Aged | |
dc.subject.mesh | Models, Molecular | |
dc.subject.mesh | Pedigree | |
dc.subject.mesh | Point Mutation | |
dc.subject.mesh | RNA, Messenger | |
dc.subject.mesh | RNA-Binding Proteins | |
dc.subject.mesh | Recombinant Fusion Proteins | |
dc.subject.mesh | Response Elements | |
dc.subject.mesh | Syndrome | |
dc.title | A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome. | en |
dc.type | Article | en |
dc.contributor.department | Cell Biology Laboratory, Department of Biochemistry, University College Cork, Cork, Ireland. caowei_111@yahoo.com.cn | en |
dc.identifier.journal | Blood cells, molecules & diseases | en |
dc.description.province | Munster | |
html.description.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. |