Blue cone monochromacy: Causative mutations and associated phenotypes

[摘要] Purpose: To perform a phenotypicassessment of members of three British families with blue conemonochromatism (BCM), and to determine the underlying molecular geneticbasis of disease. Methods: Affected members of threeBritish families with BCM were examined clinically and underwentdetailed electrophysiological and psychophysical testing. Blood sampleswere taken for DNA extraction. Molecular analysis involved theamplification of the coding regions of the long (L) and medium (M) wavecone opsin genes and the upstream locus control region (LCR) bypolymerase chain reaction (PCR). Gene products were directly sequencedand analyzed. Results: In all three families, geneticanalysis identified that the underlying cause of BCM involved anunequal crossover within the opsin gene array, with an inactivatingmutation. Family 1 had a single 5′-L–M-3′ hybrid gene, with aninactivating Cys203Arg (C203R) mutation. Family 3 had an array composedof a C203R inactivated 5′-L–M-3′ hybrid gene followed by a secondinactive gene. Families 1 and 3 had typical clinical,electrophysiological, and psychophysical findings consistent withstationary BCM. A novel mutation was detected in Family 2 that had asingle hybrid gene lacking exon 2. This family presented clinical andpsychophysical evidence of a slowly progressive phenotype. Conclusions: Two of the BCM-causingfamily genotypes identified in this study comprised different hybridgenes, each of which contained the commonly described C203Rinactivating mutation. The genotype in the family with evidence of aslowly progressive phenotype represents a novel BCM mutation. Thedeleted exon 2 in this family is not predicted to result in a shift inthe reading frame, therefore we hypothesize that an abnormal opsinprotein product may accumulate and lead to cone cell loss over time.This is the first report of slow progression associated with this classof mutation in the L or M opsin genes in BCM.

[学科分类] 生物化学/生物物理