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K. M. Berry, O. J. Lehmann, A. J. Waskiewicz; 18q Deletion Syndrome: Finding the Causative Gene for Ocular Phenotypes. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1652.
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18q deletion syndrome is characterized by strabismus, nystagmus and retinal anomalies, together with broader phenotypes that include facial dysmorphism, neurological defects and mental retardation. Since the molecular basis of these ocular phenotypes remains incompletely defined, we investigated a patient with this syndrome, to provide insight into the gene(s) responsible.
Array CGH was initially used to define the deletion’s extent, followed by bioinformatic analysis of the encompassed genes. Subsequently, zebrafish in situ hybridization and morpholino oligonucleotides were used to determine localization of mRNA and the effect of inhibiting genes of interest. The morpholino-induced phenotypes were characterized with a range of techniques including sectioning, antibody and phalloidin stains, with analyses of islet1-gfp transgenic embryos used to investigate cranial motor neuron development and migration.
Of the 15 genes lying within or adjacent to the deletion, three (adnp2, ctdp1 and sall3) were studied further due to results of bioinformatic analysis. In situ analysis and morpholino knockdown implicated sall3 in these phenotypes and based on these results, plus the known involvement of Drosophila gene sal in eye development, we focused on sall3. Zebrafish sall3 is ubiquitously expressed at a basal level, with high levels in the presumptive motor neurons. Morpholino inhibition of sall3 results in pan-ocular anomalies extending from the cornea to the retinal pigment epithelium, and a profound loss of ocular and facial muscles with aberrant development of cranial motor neurons including the oculomotor and trochlear nerves.
The effects of decreased sall3 function in zebrafish indicate that it regulates multiple aspects of eye development, and are compatible with the ocular anomalies and facial dysmorphism of human 18q deletion syndrome. Future directions include screening panels of patients displaying phenotypes corresponding to those observed in zebrafish and characterizing interactions with other sall family members.
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