Purchase this article with an account.
M. Ye, K. Berry, M. Asai-Coakwell, A. J. Waskiewicz, O. J. Lehmann; Characterization of a Novel Bmp Ligand in Ocular Disease. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2327.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
We previously demonstrated that GDF6 mutation and copy number changes underlie upto 1% of microphthalmia/anophthalmia/coloboma (MAC) disorders. In view of incomplete penetrance observed in several pedigrees, we investigated whether other bone morphogenetic proteins (BMPs) modulate or contribute to such phenotypes.
To identify candidate genes, a 6500 patient chromosomal anomaly database was screened to identify patients with: deletions encompassing BMP ligands or antagonists, and ocular phenotypes. The expression pattern of the two strongest candidates was determined with zebrafish in situ hybridization, prior to screening DNA samples for mutations in one gene (BMPx). The biochemical effects of the mutations identified were studied with western blots and the effect of morpholino inhibition of zebrafish BMPx determined.
Four heterozygous BMPx mis-sense mutations were identified in 472 MAC patients that were absent from at least 200 normal controls. Two mutations affected residues invariant in all mammalian orthologs, and one inserts an extra cysteine that changes the classification of this BMP. Notably one patient was identified who is a compound GDF6-BMPx heterozygote. Mutations in BMPx result in a spectrum of ocular (iris and retino-choroidal coloboma, microphthalmia) and skeletal (vertebral fusions and scoliosis) anomalies. Western blot analysis demonstrated the mutations reduced the amount of mature protein in both cell lysate and culture medium. Zebrafish in situ hybridization revealed expression patterns that accorded with the patient phenotypes, whilst morpholino inhibition resulted in coloboma, microphthalmia and somite anomalies.
Our data identify a new BMP member involved in ocular development and demonstrate a broad spectrum of phenotypes associated with biochemically characterized mutations. These results extend understanding of certain pediatric ophthalmic phenotypes, provide excellent animal models for more detailed study, and by identifying compound heterozygous mutations suggest the existence of more complex inheritance patterns.
This PDF is available to Subscribers Only