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C McMahon, M Neitz, J Neitz; Evaluating the Human X-Chromosome Pigment Gene Promoter Sequence as a Predictor of L:M Cone Ratio Variation . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3791.
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Purpose: The molecular mechanisms by which a cone cell chooses just one L or M pigment gene for expression from the X-chromosome array are unknown. Evidence indicates that an interaction between the L or M gene upstream promoter and an enhancer element termed the Locus Control Region (LCR) is required for pigment gene expression; however it is unclear whether this interaction is directly involved in the gene choice. One hypothesis is that the LCR is directly responsible for gene choice. In this scenario, the enhancer binds to transcription factors and enhancer binding proteins in a stochastic fashion to form a stable complex with either the L or M gene promoter. This occurs once in the life of a cell, during development. In this model, the probability of the LCR forming a stable complex with an L vs. M gene promoter might depend on the efficiency with which a promoter can recruit and stably bind the required proteins. Thus, nucleotide polymorphisms that affect protein/DNA binding to the L or M promoter could be responsible for the large variation in L:M cone ratios observed in normal humans. To test this, we sequenced the L and M gene promoters in 80 human males. Methods: An ABI Prism 310 Genetic Analyzer was used to directly sequence PCR amplified L and M pigment gene promoters (a region of ∼200 base pairs immediately upstream of exon 1). Results: The L:M cone ratios of the 80 males were estimated to vary from less than 1:1 L:M to more than 10:1. There was not corresponding variation in the promoter sequences. All of the M gene promoters were identical, as were 78 of the L gene promoters. Two L promoter sequences had one nucleotide each that was different from the majority. Interestingly, one of the variant subjects had an extremely low L:M cone ratio, while the other (with a different nucleotide substitution) had a high L:M cone ratio. Conclusion: Polymorphisms in the L and M gene promoters are present at a low rate in the color normal male population. We do not rule out the possibility that nucleotide substitutions in the promoter region can produce large changes in L:M cone ratio. However, there are large individual differences in cone ratio that occur in the absence of any variation in the promoter. There must be other DNA regions involved in determining cone ratio that vary to produce the majority of the normal cone ratio variation.
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