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Functional characterization of a novel non-coding mutation 'Ghent +49A>G' in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome

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Abstract
Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron responsive element (IRE) in the 5’ untranslated region (5’UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5’UTR mutation c.-151A>G, also named “Ghent +49A>G”. The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A>G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A>G mutation, the zygosity of which correlated well with the disease expression.
Keywords
consanguinity, disease genetics, DNA sequencing, functional genomics, genetic testing, MESSENGER-RNA, LIGHT-CHAIN, MOLECULAR FINDINGS, WEB SERVER, BINDING, GENE, PHENOTYPE, FAMILIES, LENS

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Chicago
Van De Sompele, Stijn, Lucie Pécheux, Jorge Couso, Audrey Meunier, Mayka Sanchez, and Elfride De Baere. 2017. “Functional Characterization of a Novel Non-coding Mutation ‘Ghent +49A>G’ in the Iron-responsive Element of L-ferritin Causing Hereditary Hyperferritinaemia-cataract Syndrome.” Scientific Reports 7.
APA
Van De Sompele, S., Pécheux, L., Couso, J., Meunier, A., Sanchez, M., & De Baere, E. (2017). Functional characterization of a novel non-coding mutation “Ghent +49A>G” in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome. SCIENTIFIC REPORTS, 7.
Vancouver
1.
Van De Sompele S, Pécheux L, Couso J, Meunier A, Sanchez M, De Baere E. Functional characterization of a novel non-coding mutation “Ghent +49A>G” in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome. SCIENTIFIC REPORTS. 2017;7.
MLA
Van De Sompele, Stijn, Lucie Pécheux, Jorge Couso, et al. “Functional Characterization of a Novel Non-coding Mutation ‘Ghent +49A>G’ in the Iron-responsive Element of L-ferritin Causing Hereditary Hyperferritinaemia-cataract Syndrome.” SCIENTIFIC REPORTS 7 (2017): n. pag. Print.
@article{8542419,
  abstract     = {Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron responsive element (IRE) in the 5{\textquoteright} untranslated region (5{\textquoteright}UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5{\textquoteright}UTR mutation c.-151A{\textrangle}G, also named {\textquotedblleft}Ghent +49A{\textrangle}G{\textquotedblright}. The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A{\textrangle}G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A{\textrangle}G mutation, the zygosity of which correlated well with the disease expression.},
  articleno    = {18025},
  author       = {Van De Sompele, Stijn and P{\'e}cheux, Lucie and Couso, Jorge and Meunier, Audrey and Sanchez, Mayka and De Baere, Elfride},
  issn         = {2045-2322},
  journal      = {SCIENTIFIC REPORTS},
  keyword      = {consanguinity,disease genetics,DNA sequencing,functional genomics,genetic testing,MESSENGER-RNA,LIGHT-CHAIN,MOLECULAR FINDINGS,WEB SERVER,BINDING,GENE,PHENOTYPE,FAMILIES,LENS},
  language     = {eng},
  pages        = {10},
  title        = {Functional characterization of a novel non-coding mutation 'Ghent +49A{\textrangle}G' in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome},
  url          = {http://dx.doi.org/10.1038/s41598-017-18326-6},
  volume       = {7},
  year         = {2017},
}

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