Anophthalmia, microphthalmia and coloboma (MAC) are birth defects in which the eyes are absent or very small, or where the choroid fissure fails to close during optic cup development. Most cases are sporadic, but autosomal recessive, dominant and X-linked inheritance patterns have been described, often with reduced penetrance. Mutations in few genes have been identified, including transcription factors PAX6, CHX10, RX, SOX2 and OTX2, and growth factors GDF6 and BMP4. These are expressed during critical early stages of development, when the eye field is established and the optic primordia expands. However, most cases remain unexplained. We have defined a new locus for autosomal dominant MAC by linkage analysis in a large pedigree.
We aim to refine the map position and identify the causative mutation within the nonrecombinant region. We have also discovered new categories of PAX6 and SOX gene rearrangements in children with severe bilateral microphthalmia or anophthalmia.
We aim to characterize these mutations in detail, test the mechanism of pathogenesis, and systematically screen a cohort of MAC patients genome-wide for related mutations. Finally, we have defined three modifiers of the mouse eyeless mutation (ey1), a recessive hypomorphic allele in the Rx homeobox gene that decreases abundance of the Rx polypeptide in the ZRDCT strain, creating a sensitized background to identify additional MAC genes in this animal model (Tucker et al. 2001). These modifier loci (ey2, ey3, ey4) are necessary for expression of the anophthalmia trait and exhibit strong pairwise interactions in an F2 cross. Positional candidate genes have been identified, including one required for morphogenesis of the ventral optic cup, and two antagonists of the Wnt signaling pathway, which is known to restrict the eye field in metazoans. We propose these modifiers enhance penetrance of the eyeless trait by increasing Wnt activity within head ectoderm.
We aim to refine the mapping of ey2-ey4, and test this hypothesis using specific targeted mutations and conditional knockout mice.
We will find mutations that cause the eyes to be absent (anophthalmia), very small or severely malformed (coloboma) at birth. We will use genetic linkage analysis to test pedigrees with multiple affected children, and will determine the molecular basis of these disorders. We will also test specific gene interactions that produce an eyeless trait in laboratory mice. These studies explore the earliest steps in eye formation. Our results will improve diagnosis and understanding of human eye malformations, and the complex genetic factors underlying birth defects.
|Chou, Christopher M; Nelson, Christine; Tarlé, Susan A et al. (2015) Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease. Cell 161:634-646|
|Hufnagel, Robert B; Riesenberg, Amy N; Quinn, Malgorzata et al. (2013) Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit. Mol Cell Neurosci 54:108-20|
|Slavotinek, Anne M; Mehrotra, Pavni; Nazarenko, Irina et al. (2013) Focal facial dermal dysplasia, type IV, is caused by mutations in CYP26C1. Hum Mol Genet 22:696-703|
|Kloss, Bethany A Volkmann; Reis, Linda M; Brémond-Gignac, Dominique et al. (2012) Analysis of FOXD3 sequence variation in human ocular disease. Mol Vis 18:1740-9|
|Prasov, Lev; Masud, Tehmina; Khaliq, Shagufta et al. (2012) ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Hum Mol Genet 21:3681-94|