Functional characterization of a novel non-coding mutation "Ghent +49A > G" in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Van de Sompele, Stijn; Pécheux, Lucie; Couso, Jorge; Meunier, Audrey; Sanchez, Mayka; De Baere, Elfride
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 10
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-18326-6
• Languages: English
• ISSNs: 2045-2322

Abstract

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 ofFTL 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 ofFTL . Overall, we have expanded the repertoire of deleterious biallelicFTL IRE mutations in HHCS with this novel +49A > G mutation, the zygosity of which correlated well with the disease expression.