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Sci Rep. 2017 Dec 21;7(1):18025. doi: 10.1038/s41598-017-18326-6.

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

Author information

1
Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium.
2
Department of Pediatrics, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium.
3
Program of Predictive and Personalized Medicine of Cancer, Germans Trias and Pujol Research Institute (PMPPC-IGTP), Campus Can Ruti, Badalona, Spain.
4
Iron metabolism: regulation and diseases group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias i Pujol, Badalona, Spain.
5
Department of Ophthalmology, Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium.
6
Program of Predictive and Personalized Medicine of Cancer, Germans Trias and Pujol Research Institute (PMPPC-IGTP), Campus Can Ruti, Badalona, Spain. msanchez@carrerasresearch.org.
7
Iron metabolism: regulation and diseases group, Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias i Pujol, Badalona, Spain. msanchez@carrerasresearch.org.
8
Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium. elfride.debaere@ugent.be.

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.

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