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AlphaA-crystallin R49Cneo mutation influences the architecture of lens fiber cell membranes and causes posterior and nuclear cataracts in mice.

Andley UP - BMC Ophthalmol (2009)

Bottom Line: AlphaA-crystallin (CRYAA/HSPB4), a major component of all vertebrate eye lenses, is a small heat shock protein responsible for maintaining lens transparency.By 3 weeks, WT/R49Cneo mice exhibited large vacuoles in the cortical region 100 mum from the lens surface, and by 3 months posterior and nuclear cataracts had developed.It is apparent that modification of membrane and cell-cell interactions occurs in the presence of the alphaA-crystallin mutation and rapidly leads to lens cell pathology in vivo.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri, USA. andley@vision.wustl.edu

ABSTRACT

Background: AlphaA-crystallin (CRYAA/HSPB4), a major component of all vertebrate eye lenses, is a small heat shock protein responsible for maintaining lens transparency. The R49C mutation in the alphaA-crystallin protein is linked with non-syndromic, hereditary human cataracts in a four-generation Caucasian family.

Methods: This study describes a mouse cataract model generated by insertion of a neomycin-resistant (neor) gene into an intron of the gene encoding mutant R49C alphaA-crystallin. Mice carrying the neor gene and wild-type Cryaa were also generated as controls. Heterozygous knock-in mice containing one wild type gene and one mutated gene for alphaA-crystallin (WT/R49Cneo) and homozygous knock-in mice containing two mutated genes (R49Cneo/R49Cneo) were compared.

Results: By 3 weeks, WT/R49Cneo mice exhibited large vacuoles in the cortical region 100 mum from the lens surface, and by 3 months posterior and nuclear cataracts had developed. WT/R49Cneo mice demonstrated severe posterior cataracts at 9 months of age, with considerable posterior nuclear migration evident in histological sections. R49Cneo/R49Cneo mice demonstrated nearly complete lens opacities by 5 months of age. In contrast, R49C mice in which the neor gene was deleted by breeding with CreEIIa mice developed lens abnormalities at birth, suggesting that the neor gene may suppress expression of mutant R49C alphaA-crystallin protein.

Conclusion: It is apparent that modification of membrane and cell-cell interactions occurs in the presence of the alphaA-crystallin mutation and rapidly leads to lens cell pathology in vivo.

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Related in: MedlinePlus

Morphological alterations in lenses from older wild type and R49Cneo/R49Cneo knock-in mice. (A) Lens from wild type 10-month-old mouse with normal fiber cells near the lens surface and normal appearing fibers. (B) Large swollen cells and gaps between fiber cells in lens from 10-month-old R49Cneo/R49Cneo mouse. (C) The swollen fiber cells increased in both size and number with increased age, and extended towards the center of the lens. The number of swollen cells per lens section is shown.
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Figure 8: Morphological alterations in lenses from older wild type and R49Cneo/R49Cneo knock-in mice. (A) Lens from wild type 10-month-old mouse with normal fiber cells near the lens surface and normal appearing fibers. (B) Large swollen cells and gaps between fiber cells in lens from 10-month-old R49Cneo/R49Cneo mouse. (C) The swollen fiber cells increased in both size and number with increased age, and extended towards the center of the lens. The number of swollen cells per lens section is shown.

Mentions: The number of swollen fiber cells increased in lenses of older homozygous mice, and extended towards the center of the lens (Figure 8). At 10 months old, a large area of aberrant fiber cells was observed. Fiber cells near the lens surface appeared normal. Newly synthesized cortical fibers appeared to form normally, but vacuoles were apparent in a band of fibers in the deep cortex 100 μm from lens surface, and increased dramatically towards the lens center.


AlphaA-crystallin R49Cneo mutation influences the architecture of lens fiber cell membranes and causes posterior and nuclear cataracts in mice.

Andley UP - BMC Ophthalmol (2009)

Morphological alterations in lenses from older wild type and R49Cneo/R49Cneo knock-in mice. (A) Lens from wild type 10-month-old mouse with normal fiber cells near the lens surface and normal appearing fibers. (B) Large swollen cells and gaps between fiber cells in lens from 10-month-old R49Cneo/R49Cneo mouse. (C) The swollen fiber cells increased in both size and number with increased age, and extended towards the center of the lens. The number of swollen cells per lens section is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724435&req=5

Figure 8: Morphological alterations in lenses from older wild type and R49Cneo/R49Cneo knock-in mice. (A) Lens from wild type 10-month-old mouse with normal fiber cells near the lens surface and normal appearing fibers. (B) Large swollen cells and gaps between fiber cells in lens from 10-month-old R49Cneo/R49Cneo mouse. (C) The swollen fiber cells increased in both size and number with increased age, and extended towards the center of the lens. The number of swollen cells per lens section is shown.
Mentions: The number of swollen fiber cells increased in lenses of older homozygous mice, and extended towards the center of the lens (Figure 8). At 10 months old, a large area of aberrant fiber cells was observed. Fiber cells near the lens surface appeared normal. Newly synthesized cortical fibers appeared to form normally, but vacuoles were apparent in a band of fibers in the deep cortex 100 μm from lens surface, and increased dramatically towards the lens center.

Bottom Line: AlphaA-crystallin (CRYAA/HSPB4), a major component of all vertebrate eye lenses, is a small heat shock protein responsible for maintaining lens transparency.By 3 weeks, WT/R49Cneo mice exhibited large vacuoles in the cortical region 100 mum from the lens surface, and by 3 months posterior and nuclear cataracts had developed.It is apparent that modification of membrane and cell-cell interactions occurs in the presence of the alphaA-crystallin mutation and rapidly leads to lens cell pathology in vivo.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri, USA. andley@vision.wustl.edu

ABSTRACT

Background: AlphaA-crystallin (CRYAA/HSPB4), a major component of all vertebrate eye lenses, is a small heat shock protein responsible for maintaining lens transparency. The R49C mutation in the alphaA-crystallin protein is linked with non-syndromic, hereditary human cataracts in a four-generation Caucasian family.

Methods: This study describes a mouse cataract model generated by insertion of a neomycin-resistant (neor) gene into an intron of the gene encoding mutant R49C alphaA-crystallin. Mice carrying the neor gene and wild-type Cryaa were also generated as controls. Heterozygous knock-in mice containing one wild type gene and one mutated gene for alphaA-crystallin (WT/R49Cneo) and homozygous knock-in mice containing two mutated genes (R49Cneo/R49Cneo) were compared.

Results: By 3 weeks, WT/R49Cneo mice exhibited large vacuoles in the cortical region 100 mum from the lens surface, and by 3 months posterior and nuclear cataracts had developed. WT/R49Cneo mice demonstrated severe posterior cataracts at 9 months of age, with considerable posterior nuclear migration evident in histological sections. R49Cneo/R49Cneo mice demonstrated nearly complete lens opacities by 5 months of age. In contrast, R49C mice in which the neor gene was deleted by breeding with CreEIIa mice developed lens abnormalities at birth, suggesting that the neor gene may suppress expression of mutant R49C alphaA-crystallin protein.

Conclusion: It is apparent that modification of membrane and cell-cell interactions occurs in the presence of the alphaA-crystallin mutation and rapidly leads to lens cell pathology in vivo.

Show MeSH
Related in: MedlinePlus