Differences in corneal phenotypes between destrin mutants are due to allelic difference and modified by genetic background.

Abstract

PURPOSE:

Mutations in destrin (Dstn) cause corneal abnormalities in mice. A null mutation, Dstn(corn1), results in corneal epithelial hyperproliferation, inflammation, and neovascularization in the A.BY background (A.BY Dstn(corn1)). Homozygosity for a point mutation, Dstn(corn1-2J), results in mild thickening of the corneal epithelium but no corneal neovascularization in a C57BL/6 (B6) background (B6 Dstn(corn1-2J)). The goal of this study was to determine whether phenotypic differences are due to allelic differences between Dstn(corn1) and Dstn(corn1-2J), or are the result of genetic background effects.

METHODS:

We generated two congenic (Cg) mouse lines, B6.Cg-Dstn(corn1) and A.BY.Cg-Dstn(corn1-2J), to compare to the original A.BY Dstn(corn1) and B6 Dstn(corn1-2J) lines. We performed immunohistochemistry to assay F-actin accumulation, neovascularization, proliferation, and inflammation. By western blot analysis we tested the expression of serum response factor (SRF), a known regulator of the Dstn(corn1) phenotype.

RESULTS:

The Dstn(corn1) mutation leads to neovascularization, hyperproliferation, and inflammation in the cornea of A.BY Dstn(corn1) as well as B6.Cg-Dstn(corn1) mice. We did not observe significant corneal neovascularization or hyperproliferation in either A.BY.Cg-Dstn(corn1-2J) or B6 Dstn(corn1-2J) mice. Actin accumulation, neovascularization, epithelial proliferation and inflammation in B6.Cg-Dstn(corn1) cornea are significantly reduced when compared to A.BY Dstn(corn1)cornea. SRF changes are consistent in Dstn(corn1) mutants, regardless of genetic background.

CONCLUSIONS:

Differences in the abnormal phenotypes of Dstn mutants result from allelic differences between Dstn(corn1) and Dstn(corn1-2J) . Moreover, phenotypes of Dstn(corn1) mice are modified by genetic background, suggesting the existence of genetic modifiers. Protein analysis suggests that a genetic modifier affects phenotypic severity functionally downstream from or in a pathway independent from SRF. These data demonstrate that natural genetic variation affects phenotypic severity in Dstn(corn1) mice.

• Authors: Sharolyn V Kawakami-Schulz, Angela M Verdoni, Shannon G Sattler, Akihiro Ikeda, Sakae Ikeda
• Journal: Molecular vision (Mol Vis) Vol. 18 Pg. 606-16 ( 2012) ISSN: 1090-0535 [Electronic] United States
• PMID: 22419854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Actins
• Destrin
• Dstn protein, mouse
• Protein Kinases
• serum response factor kinase

Topics

• Actins (genetics, metabolism)
• Alleles
• Animals
• Cornea (blood supply, metabolism, pathology)
• Corneal Neovascularization (genetics, metabolism)
• Destrin (genetics, metabolism)
• Founder Effect
• Gene Expression
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• Mice
• Mice, Transgenic
• Mutation
• Phenotype
• Protein Kinases (genetics, metabolism)
• Severity of Illness Index