GENETIC-HETEROGENEITY AMONG BLUE-CONE MONOCHROMATES

Thirty-three unrelated subjects with blue-cone monochromacy or closely related variants of blue-cone monochromacy were examined for rearrang ements in the tandem array of genes encoding the red- and green-cone p igments. In 24 subjects, eight genotypes were found that would be pred icted to eliminate the function of all of the genes within the array. As observed in an earlier study, the rearrangements involve either del etion of a locus control region adjacent to the gene array or loss of function via homologous recombination and point mutation. One inactiva ting mutation, Cys203-to-Arg, was found in 15 probands who carry singl e genes and in both visual pigment genes in one subject whose array ha s two genes. This mutation was also found in at least one of the visua l pigment genes in 1 subject whose array has multiple genes and in 2 o f 321 control subjects, suggesting that preexisting Cys203-to-Arg muta tions constitute a reservoir of chromosomes that are predisposed to ge nerate blue-cone-monochromat genotypes by unequal homologous recombina tion and/or gene conversion. Two other point mutations were identified : (a) Arg247-to-Ter in one subject with a single red-pigment gene and (b) Pro307-to-Leu in one subject with a single 5' red-3' green hybrid gene. The observed heterogeneity of genotypes points to the existence of multiple one- and two-step mutational pathways to blue-cone monochr omacy.