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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

Posterior lens defects in R49Cneo knock-in mouse. Images are shown for lens sections from 9.5-month-old WT/WTneo and WT/R49Cneo mouse. (A) Brightfield image of the equatorial region in a WT/WTneo mid-sagittal lens section. (B) Brightfield image of the equatorial region in a WT/R49Cneo mid-sagittal lens section. (C) Posterior region of a WT/WTneo lens shows a normal posterior capsule. (D) A WT/R49Cneolens with posterior cataract. Note the extensive posterior rupture, migration of cells and cell debris (arrow), and compaction of the ruptured posterior capsule (arrowhead).
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Figure 6: Posterior lens defects in R49Cneo knock-in mouse. Images are shown for lens sections from 9.5-month-old WT/WTneo and WT/R49Cneo mouse. (A) Brightfield image of the equatorial region in a WT/WTneo mid-sagittal lens section. (B) Brightfield image of the equatorial region in a WT/R49Cneo mid-sagittal lens section. (C) Posterior region of a WT/WTneo lens shows a normal posterior capsule. (D) A WT/R49Cneolens with posterior cataract. Note the extensive posterior rupture, migration of cells and cell debris (arrow), and compaction of the ruptured posterior capsule (arrowhead).

Mentions: Examples of the posterior lens changes observed in R49Cneo αA-crystallin knock-in lens sections are shown in Figures 5 and 6. Posterior cataract was evident in 3-month-old R49Cneo/R49Cneo homozygous mice. At 9 months, WT/R49Cneo heterozygous mouse lenses showed severe posterior rupture, curling up of the posterior capsule, and migration of cells to the posterior lens (Figure 6).


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)

Posterior lens defects in R49Cneo knock-in mouse. Images are shown for lens sections from 9.5-month-old WT/WTneo and WT/R49Cneo mouse. (A) Brightfield image of the equatorial region in a WT/WTneo mid-sagittal lens section. (B) Brightfield image of the equatorial region in a WT/R49Cneo mid-sagittal lens section. (C) Posterior region of a WT/WTneo lens shows a normal posterior capsule. (D) A WT/R49Cneolens with posterior cataract. Note the extensive posterior rupture, migration of cells and cell debris (arrow), and compaction of the ruptured posterior capsule (arrowhead).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Posterior lens defects in R49Cneo knock-in mouse. Images are shown for lens sections from 9.5-month-old WT/WTneo and WT/R49Cneo mouse. (A) Brightfield image of the equatorial region in a WT/WTneo mid-sagittal lens section. (B) Brightfield image of the equatorial region in a WT/R49Cneo mid-sagittal lens section. (C) Posterior region of a WT/WTneo lens shows a normal posterior capsule. (D) A WT/R49Cneolens with posterior cataract. Note the extensive posterior rupture, migration of cells and cell debris (arrow), and compaction of the ruptured posterior capsule (arrowhead).
Mentions: Examples of the posterior lens changes observed in R49Cneo αA-crystallin knock-in lens sections are shown in Figures 5 and 6. Posterior cataract was evident in 3-month-old R49Cneo/R49Cneo homozygous mice. At 9 months, WT/R49Cneo heterozygous mouse lenses showed severe posterior rupture, curling up of the posterior capsule, and migration of cells to the posterior lens (Figure 6).

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