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M. Neitz, J. Neitz, D. R. Williams, J. Carroll; Architecture of the Cone Mosaic in Carriers of Blue Cone Monochromacy Caused by Deletion of the Enhancer. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3179.
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Deletion of a transcriptional enhancer upstream of the X-chromosome cone opsin gene array accounts for about 40% of Blue Cone Monochromacy (BCM). Without the enhancer, adjacent intact L and M opsin genes can not be expressed but whether affected L and M cones are present but lack outer segments versus absent is unknown. This question can be addressed in female carriers of BCM because the random process of X inactivation is expected to produce a subset of cones that have BCM-X-chromosome active. If affected cones in female carriers are present but lack outer segments, gaps in the cone mosaic visualized with adaptive optics would be expected; however, if the cones are absent, a reduced cone number and cone density is expected.
The polymerase chain reaction and DNA sequencing was used to define the deletion endpoints in males with BCM. Female relatives were screened for the presence of the characterized deletions. Three BCM carriers and two non-carriers from two unrelated families were identified, and adaptive optics was used to obtain high resolution images of their retinas.
One family had a 52 kb deletion; the other had a 15 kb deletion. Both deletions excised the upstream enhancer and left multiple intact cone opsin genes on the X-chromosome. Two carriers and one non-carrier from the family with the 15 kb deletion, and one carrier and one non-carrier from the family with the 52 kb deletion were identified. Compared to their non-carrier female relatives and unaffected controls, carriers had reduced foveal cone densities.
L and M cones in carriers of BCM that retain the affected X-chromosome as the active X cannot express normal levels of L or M opsin. Notwithstanding the well documented normal variability in foveal cone density, the BCM carriers had a reduced foveal cone density compared to unaffected controls. The reduced cone density in carriers is consistent with the hypothesis that cones that choose to retain the BCM-carrying X-chromosome as active die prior to foveal migration, and that during foveal development, cone packing occurs in a manner that allows the surviving cones to occupy all of the available space in the fovea. Whether cones expand into all available space in the peripheral retina is still an open question. Finally, adaptive optics imaging has proven to be an effective non-invasive means of identifying carriers of BCM, which may have value for genetic counseling of prospective mothers.
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