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M. Ye, M. Asai-coakwell, C. French, A. Waskiewicz, O. Lehmann; Identification of a New Tgf-beta Family Member Associated With Ocular Anomalies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):447.
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We previously demonstrated the role of one member of the BMP subfamily in causing microphthalmia /anophthalmia /coloboma (MAC) disorders. In view of the incompletely penetrant phenotypes observed in some pedigrees, we investigated whether other members of this large TGF-beta family might modulate, or contribute to, such phenotypes.
To identify candidate genes, a large chromosomal anomaly database was first screened for patients with ocular phenotypes and segmental deletions encompassing TGF-beta family members. Subsequently, a small cohort of MAC patients was screened for mutations in a subset of these genes and in situ hybridization of 20-somite stage zebrafish performed to assess their expression pattern.
A heterozygous mutation in one TGF-beta family member was observed in 1 of 36 MAC patients, which was absent from 152 control individuals (p<0.05). This missense mutation replaces an evolutionary conserved amino acid with a cysteine. In situ hybridization of the zebrafish paralogue reveals ocular (and hindbrain) expression that is compatible with the patients’ unilateral iris and retino-choroidal coloboma phenotype.
Our preliminary data have identified a single mutation in a little studied member of the TGF-beta family. Insertion of a cysteine is likely pathogenic due to cysteine’s known role in disulphide bond formation and ligand dimerization - indeed their numbers are so evolutionarily conserved that they form the basis of sub-classifying TGF-beta family members. Our ongoing studies include screening a larger panel of patients with MAC phenotypes for mutations in this gene and determining the effect of inhibiting its function with morpholino oligonucleotides.
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