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Sonya Widen, Prajakta Desai, Mika Asai-Coakwell, Matthew Benson, Curtis French, Ordan J Lehmann, Andrew Waskiewicz; Identification of a novel cause of ocular coloboma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):900.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular coloboma results from the incomplete fusion of the optic fissure and is a major cause of pediatric vision loss. We investigated a microphthalmia, anophthalmia and coloboma (MAC) cohort to advance understanding of these disorders’ genetic etiology.
Exomic next generation sequencing (NGS) was performed in a large coloboma pedigree and the mutated gene was subsequently screened in 150 MAC DNA samples. Luciferase reporter assays, western blots and in silico ANOLEA modeling were used to investigate the pathogenicity of the identified mutations. Zebrafish morpholino (MO) inhibition was used to investigate gene function together with in situ hybridization (ISH), and analysis of transgenic GFP reporter lines.
NGS identified a BMP3 mutation in affected individuals of the MAC pedigree. The identified variant, A470P, alters a residue that is invariant across vertebrates. Four additional variants were identified in the larger cohort (A188D, K345N, S393F, F450Y), all of which were absent from controls. Consistent with these variants being disease causing, western immunoblots and luciferase reporter assays demonstrate significantly altered activity relative to wildtype BMP3. Supporting bmp3’s role in ocular development, antisense MO inhibition induces zebrafish coloboma and lens defects (85%, N=46). Furthermore, we show that bmp3 is expressed in a neural crest subpopulation (periocular mesenchyme, POM) with a critical role in eye development. Although POM migration to the eye in bmp3 morphants is unaffected, analysis of BMPRE:GFP (BMP Responsive Element) transgenics demonstrates retinal BMP signaling is profoundly altered (90%, N=10).
We have identified a novel gene involved in MAC disorders, BMP3. While the precise regulation of ocular BMPs is required for optic fissure closure, BMP3’s role in eye development and disease is unstudied. Our research extends the role of BMPs in eye development and implicates BMP signaling in POM in this process. These data are compatible with a model in which POM bmp3 regulates retinal BMP signaling, identifying a mechanism for bmp3 in eye development and MAC disorders.
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