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

ABSTRACT: BACKGROUND: Hereditary 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: The 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.

SUBMITTER: Luscieti S

PROVIDER: S-EPMC3585816 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Luscieti Sara S Tolle Gabriele G Aranda Jessica J Campos Carmen Benet CB Risse Frank F Morán Érica É Muckenthaler Martina U MU Sánchez Mayka M

Orphanet journal of rare diseases 20130219

<h4>Background</h4>Hereditary 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.<h4>Methods</h4>We describe two families presenting high serum ferritin levels and juvenile cataract with ...[more]

PMID: 23421845

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Project description:Cataract is a clinically and genetically heterogeneous disorder of the ocular lens and an important cause of visual impairment. The aim of this study was to map and identify the gene underlying autosomal dominant cataract segregating in a four-generation family, determine the lens expression profile of the identified gene, and test for its association with age-related cataract in a case-control cohort.Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single-nucleotide polymorphism markers and microsatellite markers. Linkage analyses were performed using the GeneHunter and MLINK programs, and mutation detection was achieved by dideoxy cycle sequencing. Lens expression studies were performed using reverse-transcription polymerase chain reaction (RT-PCR) and in situ hybridization.Genome-wide linkage analysis with single nucleotide polymorphism markers in the family identified a likely disease-haplotype interval on chromosome 19q (rs888861-[~17Mb]-rs8111640) that encompassed the microsatellite marker D19S879 (logarithm of the odds score [Z]=2.03, recombination distance [?]=0). Mutation profiling of positional-candidate genes detected a heterozygous, noncoding G-to-T transversion (c.-168G>T) located in the iron response element (IRE) of the gene coding for ferritin light chain (FTL) that cosegregated with cataract in the family. Serum ferritin levels were found to be abnormally elevated (~fourfold), without evidence of iron overload, in an affected family member; this was consistent with a diagnosis of hereditary hyperferritinemia-cataract syndrome. No sequence variations located within the IRE were detected in a cohort of 197 cases with age-related cataract and 102 controls with clear lenses. Expression studies of human FTL, and its mouse counterpart FTL1, in the lens detected RT-PCR amplicons containing full-length protein-coding regions, and strong in situ localization of FTL1 transcripts to the lens equatorial epithelium and peripheral cortex.The data are consistent with robust transcription of FTL in the lens, and suggest that whereas variations clustered in the IRE of the FTL gene are directly associated with hereditary hyperferritinemia-cataract syndrome, such IRE variations are unlikely to play a significant role in the genetic etiology of age-related cataract.

Project description:Cellular growth, function, and protection require proper iron management, and ferritin plays a crucial role as the major iron sequestration and storage protein. Ferritin is a 24 subunit spherical shell protein composed of both light (FTL) and heavy chain (FTH1) subunits, possessing complimentary iron-handling functions and forming three-fold and four-fold pores. Iron uptake through the three-fold pores is well-defined, but the unloading process somewhat less and generally focuses on lysosomal ferritin degradation although it may have an additional, energetically efficient pore mechanism. Hereditary Ferritinopathy (HF) or neuroferritinopathy is an autosomal dominant neurodegenerative disease caused by mutations in the FTL C-terminal sequence, which in turn cause disorder and unraveling at the four-fold pores allowing iron leakage and enhanced formation of toxic, improperly coordinated iron (ICI). Histopathologically, HF is characterized by iron deposition and formation of ferritin inclusion bodies (IBs) as the cells overexpress ferritin in an attempt to address iron accumulation while lacking the ability to clear ferritin and its aggregates. Overexpression and IB formation tax cells materially and energetically, i.e., their synthesis and disposal systems, and may hinder cellular transport and other spatially dependent functions. ICI causes cellular damage to proteins and lipids through reactive oxygen species (ROS) formation because of high levels of brain oxygen, reductants and metabolism, taxing cellular repair. Iron can cause protein aggregation both indirectly by ROS-induced protein modification and destabilization, and directly as with mutant ferritin through C-terminal bridging. Iron release and ferritin degradation are also linked to cellular misfunction through ferritinophagy, which can release sufficient iron to initiate the unique programmed cell death process ferroptosis causing ROS formation and lipid peroxidation. But IB buildup suggests suppressed ferritinophagy, with elevated iron from four-fold pore leakage together with ROS damage and stress leading to a long-term ferroptotic-like state in HF. Several of these processes have parallels in cell line and mouse models. This review addresses the roles of ferritin structure and function within the above-mentioned framework, as they relate to HF and associated disorders characterized by abnormal iron accumulation, protein aggregation, oxidative damage, and the resulting contributions to cumulative cellular stress and death.

Dataset Information

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

Publications

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

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