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Ferritin crystal cataracts in hereditary hyperferritinemia cataract syndrome
David G Brooks1, Katia Manova-Todorova, Jennifer Farmer
1Division of Medical Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. brooksda@mail.med.upenn.edu
Insights
Hereditary hyperferritinemia cataract syndrome (HHCS) causes cataracts due to light-diffracting ferritin crystals. A novel L-ferritin gene mutation was identified in a US family, explaining the condition.
Area of Science:
- Ophthalmology
- Genetics
- Biochemistry
Background:
- Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare genetic disorder.
- It is characterized by elevated ferritin levels, cataracts, and mutations in the ferritin light-chain (L-ferritin) gene.
Purpose of the Study:
- To diagnose HHCS in a US family and determine the cause of lens opacities.
- To investigate a novel L-ferritin gene mutation and its functional impact.
Main Methods:
- DNA sequencing of the L-ferritin gene for mutation detection.
- RNA electrophoretic mobility shift assay to assess mutation effects.
- Immunohistochemistry and electron microscopy of lens aspirate to characterize opacities.
Main Results:
- A novel C33T mutation in the L-ferritin gene was identified in five affected family members.
- The mutation disrupted L-ferritin transcript function.
- Light-diffracting ferritin crystals were found in cataractous lenses, confirming their role in HHCS.
Conclusions:
- HHCS-related cataracts result from light-diffracting ferritin crystals in the lens cortex.
- Family history of cataracts and hyperferritinemia (without high iron) can indicate HHCS.
Purpose:
Hereditary hyperferritinemia cataract syndrome (HHCS) is a genetic disease defined by cataracts, hyperferritinemia, and ferritin light-chain (L-ferritin) gene mutations. HHCS was diagnosed in this study in one of the first families known to be affected in the United States, and the basis of lens opacities in HHCS was determined.
Methods:
DNA amplification and sequencing of the human L-ferritin gene was used for mutation detection. RNA electrophoretic mobility shift analysis was performed to demonstrate functional consequences of a new mutation. Opacities were characterized by immunohistochemical and electron microscopic analyses of human HHCS lens aspirate.
Results:
HHCS was diagnosed in five members of one family who had all three hallmark features: hyperferritinemia, a prominent cataract or history, and the finding of a novel mutation in the L-ferritin gene (C33T). This mutation interferes with function of the L-ferritin transcript in an RNA gel shift assay. Light-diffracting crystalline deposits were present in cataractous lenses from two affected family members but not in control lenses. Immunohistochemical analysis showed strong anti-L-ferritin reactivity in the crystalline deposits. Analysis of these deposits by transmission electron microscopy with fast Fourier transformation demonstrated macromolecular crystalline structure of the deposits. The data were consistent with a face-centered cubic crystal having a unit crystal cell size of 17 nm, both findings characteristic of ferritin crystals grown in vitro.
Conclusions:
HHCS cataract is due to numerous small opacities, predominantly in the lens cortex, that are light-diffracting ferritin crystals. Patients with HHCS may be recognized by a family history of cataracts and hyperferritinemia without increased serum iron.