Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis.
Document Type
Article
Publication Date
2007
Keywords
Collagen-Type-IV, Endoplasmic-Reticulum, Eye-Diseases, Immunohistochemistry, Mice-Inbred-C57BL, Mice-Knockout, Microscopy-Electron-Transmission, Mutation, Optic-Nerve
First Page
798
Last Page
807
JAX Source
Hum Mol Genet 2007 Apr; 16(7):798-807.
Abstract
Ocular anterior segment dysgenesis (ASD) is a complex and poorly understood group of conditions. A large proportion of individuals with ASD develop glaucoma, a leading cause of blindness resulting from retinal ganglion cell death. Optic nerve hypoplasia is thought to have distinct causes and is a leading cause of blindness in children. Here, we show that a mutation in the type IV collagen alpha 1 (Col4a1) gene can cause both ASD and optic nerve hypoplasia. COL4A1 is a major component of almost all basement membranes. The mutation results in non-secretion of the mutant COL4A1 proteins, which instead accumulate within cells. Basement membrane abnormalities may, therefore, contribute to the phenotype. The mutation also induces endoplasmic reticulum stress and so intracellular stress may contribute to pathogenesis. The overall consequence of the Col4a1 mutation depends on genetic context. In one genetic context, the mutation causes severe ASD with intraocular pressure abnormalities and optic nerve hypoplasia. In a different genetic context, both the ASD and optic nerve hypoplasia are rescued, and we have identified a single dominant locus that confers the phenotypic modification.
Recommended Citation
Gould DB,
Marchant JK,
Savinova OV,
Smith RS,
John SW.
Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis. Hum Mol Genet 2007 Apr; 16(7):798-807.