Bilateral cataract in a subject carrying a C to A transition in the L ferritin promoter region

Faniello, Maria Concetta; Sanzo, Maddalena Di; Quaresima, Barbara; Nisticò, Antonia; Fregola, Annalisa; Grosso, Michela; Cuda, Giovanni; Costanzo, Francesco

doi:10.1016/j.clinbiochem.2009.02.013

Cited by 11 publications

(7 citation statements)

References 8 publications

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“…The majority of the causative mutations are located in the hexanucleotide loop, followed by the C-bulge region, the upper stem and the lower stem of the IRE structure (Figure 2). Other occurrences of inherited unexplained hyperferritinaemia but without cataracts or cataracts diagnosed in adult age have been attributed to mutations in the promoter region, coding region or outside the IRE motif of FTL [10,13-15]. …”

Section: Resultsmentioning

confidence: 99%

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

Luscieti

Tolle

Aranda

et al. 2013

Orphanet J Rare Dis

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BackgroundHereditary Hyperferritinaemia Cataract Syndrome (HHCS) is a rare autosomal dominant disease characterized by increased serum ferritin levels and early onset of bilateral cataract. The disease is caused by mutations in the Iron-Responsive Element (IRE) located in the 5′ untranslated region of L-Ferritin (FTL) mRNA, which post-transcriptionally regulates ferritin expression.MethodsWe describe two families presenting high serum ferritin levels and juvenile cataract with novel mutations in the L-ferritin IRE. The mutations were further characterized by in vitro functional studies.ResultsWe have identified two novel mutations in the IRE of L-Ferritin causing HHCS: the Badalona +36C > U and the Heidelberg +52 G > C mutation. Both mutations conferred reduced binding affinity on recombinant Iron Regulatory Proteins (IPRs) in EMSA experiments. Interestingly, the Badalona +36C > U mutation was found not only in heterozygosity, as expected for an autosomal dominant disease, but also in the homozygous state in some affected subjects. Additionally we report an update of all mutations identified so far to cause HHCS.ConclusionsThe Badalona +36C > U and Heidelberg +52 G > C mutations within the L-ferritin IRE only mildly alter the binding capacity of the Iron Regulatory Proteins but are still causative for the disease.

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Section: Resultsmentioning

confidence: 99%

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

Luscieti

Tolle

Aranda

et al. 2013

Orphanet J Rare Dis

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“…The human GAPDH cDNA fragment was amplified as the internal control. Data analysis was performed using the 2 -ΔΔCt [ 31 ].…”

Section: Methodsmentioning

confidence: 99%

Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis

Aversa

Zolea

Ieranò³

et al. 2017

J Exp Clin Cancer Res

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BackgroundFerritin plays a central role in the intracellular iron metabolism; the molecule is a nanocage of 24 subunits of the heavy and light types. The heavy subunit (FHC) is provided of a ferroxidase activity and thus performs the key transformation of iron in a non-toxic form. Recently, it has been shown that FHC is also involved in additional not iron-related critical pathways including, among the others, p53 regulation, modulation of oncomiRNAs expression and chemokine signalling. Epithelial to mesenchymal transition (EMT) is a cellular mechanism by which the cell acquires a fibroblast-like phenotype along with a decreased adhesion and augmented motility. In this work we have focused our attention on the role of the FHC on EMT induction in the human cell lines MCF-7 and H460 to elucidate the underlying molecular mechanisms.MethodsTargeted silencing of the FHC was performed by lentiviral-driven shRNA strategy. Reconstitution of the FHC gene product was obtained by full length FHC cDNA transfection with Lipofectamine 2000. MTT and cell count assays were used to evaluate cell viability and proliferation; cell migration capability was assayed by the wound-healing assay and transwell strategy. Quantification of the CXCR4 surface expression was performed by flow cytometry.ResultsExperimental data indicated that FHC-silenced MCF-7 and H460 cells (MCF-7shFHC, H460shFHC) acquire a mesenchymal phenotype, accompanied by a significant enhancement of their migratory and proliferative capacity. This shift is coupled to an increase in ROS production and by an activation of the CXCR4/CXCL12 signalling pathway. We present experimental data indicating that the cytosolic increase in ROS levels is responsible for the enhanced proliferation of FHC-silenced cells, while the higher migration rate is attributable to a dysregulation of the CXCR4/CXCL12 axis.ConclusionsOur findings indicate that induction of EMT, increased migration and survival depend, in MCF-7 and H460 cells, on the release of FHC control on two pathways, namely the iron/ROS metabolism and CXCR4/CXCL12 axis. Besides constituting a further confirmation of the multifunctional nature of FHC, this data also suggest that the analysis of FHC amount/function might be an important additional tool to predict tumor aggressiveness.

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“…In HHCS, it is known that the pathological molecular mechanism is linked to the disruption of the IRP-IRE post-transcriptional regulatory system, with the de-repression of L-ferritin mRNA and the subsequent overproduction of L-ferritin protein that precipitates and deposits in the lens of the eyes, producing cataracts. In HHCS, authors have argued that an association exists between the clinical severity of the disease and the location of the mutation in FTL -IRE [11,27,28]. Higher serum ferritin levels are mostly associated with mutations in the apical loop or the C-bulge area, compared with mutations in the upper or lower stems.…”

Section: Discussionmentioning

confidence: 99%

L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

Cadenas

Fita-Torró²,

Bermúdez-Cortés

et al. 2019

Pharmaceuticals

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Ferritin is a multimeric protein composed of light (L-ferritin) and heavy (H-ferritin) subunits that binds and stores iron inside the cell. A variety of mutations have been reported in the L-ferritin subunit gene (FTL gene) that cause the following five diseases: (1) hereditary hyperferritinemia with cataract syndrome (HHCS), (2) neuroferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), (3) benign hyperferritinemia, (4) L-ferritin deficiency with autosomal dominant inheritance, and (5) L-ferritin deficiency with autosomal recessive inheritance. Defects in the FTL gene lead to abnormally high levels of serum ferritin (hyperferritinemia) in HHCS and benign hyperferritinemia, while low levels (hypoferritinemia) are present in neuroferritinopathy and in autosomal dominant and recessive L-ferritin deficiency. Iron disturbances as well as neuromuscular and cognitive deficits are present in some, but not all, of these diseases. Here, we identified two novel FTL variants that cause dominant L-ferritin deficiency and HHCS (c.375+2T > A and 36_42delCAACAGT, respectively), and one previously reported variant (Met1Val) that causes dominant L-ferritin deficiency. Globally, genetic changes in the FTL gene are responsible for multiple phenotypes and an accurate diagnosis is useful for appropriate treatment. To help in this goal, we included a diagnostic algorithm for the detection of diseases caused by defects in FTL gene.

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Bilateral cataract in a subject carrying a C to A transition in the L ferritin promoter region

Cited by 11 publications

References 8 publications

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

Novel mutations in the ferritin-L iron-responsive element that only mildly impair IRP binding cause hereditary hyperferritinaemia cataract syndrome

Epithelial-to-mesenchymal transition in FHC-silenced cells: the role of CXCR4/CXCL12 axis

L-Ferritin: One Gene, Five Diseases; from Hereditary Hyperferritinemia to Hypoferritinemia—Report of New Cases

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