Genetic Mechanisms of Hyperferritinemia-Cataract Syndrome

Hereditary hyperferritinaemia-cataract syndrome is an autosomal dominant disorder characterised by constitutive overproduction of the ferritin L-subunit, leading to elevated serum ferritin levels in the absence of iron overload and early-onset bilateral cataracts. Pathogenic variants cluster within the iron response element (IRE) of the 5′ untranslated region of the FTL gene, disrupting binding of iron regulatory proteins and abolishing normal translational repression. The resulting excess L-ferritin assembles into storage complexes in lens fibres, provoking oxidative stress and opacification. A range of single-nucleotide substitutions within the IRE loop and stem has been described, each correlating with variable age at onset and cataract morphology. Modifier loci—most notably alleles of the HFE gene—appear to influence ferritin levels, suggesting a broader network of iron-homeostasis regulators. Improved understanding of these molecular pathways underpins accurate diagnosis, informs surgical timing for lens extraction and highlights the importance of family screening and genetic counselling in diverse populations worldwide.

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Technical terms

Autosomal dominant: A mode of inheritance in which a single copy of a pathogenic variant in a gene is sufficient to cause disease.

Iron response element (IRE): A conserved hairpin sequence in the untranslated region of ferritin mRNA that binds iron regulatory proteins to control translation.

Ferritin L-subunit (FTL): One of two peptide chains comprising ferritin, responsible for iron storage and cellular regulation of oxidative stress.

Iron regulatory proteins (IRP): Cytosolic proteins that bind IREs in response to cellular iron levels, modulating translation of iron-related genes.

Untranslated region (UTR): A non-coding segment of mRNA that influences post-transcriptional regulation, including stability and translational efficiency.

References

1. Genotypic–Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families. International Journal of Molecular Sciences (2023).
2. Ferritin L-subunit gene mutation and hereditary hyperferritinaemia cataract syndrome (HHCS): a case report and literature review. Hematology (2021).