Functional characterization of a novel non-coding mutation "Ghent+49A > G" in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome
Por:
Van de Sompele, S, Pecheux, L, Couso, J, Meunier, A, Sanchez, M and De Baere, E
Publicada:
21 dic 2017
Categoría:
Multidisciplinary
Resumen:
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.
Filiaciones:
Van de Sompele, S:
Ghent Univ Hosp, Dept Med Genet, Ghent, Belgium
Pecheux, L:
Univ St Pierre, Ctr Hosp, Dept Pediat, Brussels, Belgium
Couso, J:
Germans Trias & Pujol Res Inst PMPPC IGTP, Program Predict & Personalized Med Canc, Badalona, Spain
Josep Carreras Leukaemia Res Inst IJC, Iron Metab Regulat & Dis Grp, Campus ICO Germans Trias & Pujol, Badalona, Spain
Meunier, A:
Univ St Pierre, Ctr Hosp, Dept Ophthalmol, Brussels, Belgium
:
Germans Trias & Pujol Res Inst PMPPC IGTP, Program Predict & Personalized Med Canc, Badalona, Spain
Josep Carreras Leukaemia Res Inst IJC, Iron Metab Regulat & Dis Grp, Campus ICO Germans Trias & Pujol, Badalona, Spain
De Baere, E:
Ghent Univ Hosp, Dept Med Genet, Ghent, Belgium
Green Published, gold
|