Analysis of BMP3 variants in the causality of ocular coloboma

Abstract

Coloboma, a congenital disorder characterized by gaps in ocular tissues,\nis caused when the choroid fissure fails to close during embryonic\ndevelopment. Several loci have been associated with coloboma, but these\nrepresent less than 40% of those that are involved with this disease.\nHere, we describe a novel coloboma-causing locus, BMP3. Whole exome\nsequencing and Sanger sequencing of patients with coloboma identified\nthree variants in BMP3, two of which are predicted to be disease\ncausing. Consistent with this, bmp3 mutant zebrafish have aberrant\nfissure closure. bmp3 is expressed in the ventral head mesenchyme and\nregulates phosphorylated Smad3 in a population of cells adjacent to the\nchoroid fissure. Furthermore, mutations in bmp3 sensitize embryos to\nSmad3 inhibitor treatment resulting in open choroid fissures. Micro CT\nscans and Alcian blue staining of zebrafish demonstrate that mutations\nin bmp3 cause midface hypoplasia, suggesting that bmp3 regulates cranial\nneural crest cells. Consistent with this, we see active Smad3 in a\npopulation of periocular neural crest cells, and bmp3 mutant zebrafish\nhave reduced neural crest cells in the choroid fissure. Taken together,\nthis data suggests that Bmp3 controls Smad3 phosphorylation in neural\ncrest cells to regulate early craniofacial and ocular development.