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Human Molecular Genetics Advance Access published online on February 22, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm024
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Col4a1 Mutation Causes Endoplasmic Reticulum Stress and Genetically Modifiable Ocular Dysgenesis

Douglas B. Gould1,#, Jeffrey K. Marchant2, Olga V. Savinova1,3,¶, Richard S. Smith1,3 and Simon W. M. John1,3,4,*

1 The Jackson Laboratory, Bar Harbor, ME 2 Department of Anatomy & Cell Biology, Tufts University School of Medicine, Boston, MA 3 The Howard Hughes Medical Institute, Bar Harbor, ME 4 Department of Ophthalmology, Tufts University School of Medicine, Boston, MA

* To whom correspondence should be addressed: Simon W. M. John, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, 207-288-6496 (T), 207-288-6078 (F), simon.john{at}jax.org

Received November 27, 2006; Revised January 18, 2007; Accepted February 9, 2007

Ocular anterior segment dysgenesis is a complex and poorly understood group of conditions. A large proportion of individuals with anterior segment dysgenesis 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 anterior segment dysgenesis 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 anterior segment dysgenesis with intraocular pressure abnormalities and optic nerve hypoplasia. In a different genetic context, both the anterior segment dysgenesis and optic nerve hypoplasia are rescued, and we have identified a single dominant locus that confers the phenotypic modification.

# Current address: Departments of Ophthalmology and Anatomy, Institute for Human Genetics, UCSF School of Medicine, San Francisco, CA.

Current address: Department of Chemistry and Biochemistry, UCSD, La Jolla, CA.


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