Purpose: To determine the molecular basis of an early and severe form of autosomal dominant retinitis pigmentosa and to characterize the associated phenotype. Methods: Visual function evaluation included electrophysiologic and psychophysical testing. Molecular genetic analysis included determining the DNA sequence of sections of the rhodopsin gene amplified by polymerase chain reaction and screening for singlenucleotide changes by allele-specific oligonucleotide hybridization. Results: Affected family members are heterozygous for a unique Cys187Tyr rhodopsin mutation which disrupts a highly conserved disulfide bond essential to normal rhodopsin function. The retinitis pigmentosa (RP) phenotype includes early and severe retinal dysfunction. The full-field electroretinogram showed only negligible remaining rod and cone responses by 22 years of age. Visual fields were constricted severely by early middle-age years. Macular dysfunction caused reduced visual acuity in early adult years, and macular atrophy was present in older age. The severity of phenotype generally correlated with age, with the exception of an affected 44-year-old patient who had better visual acuity, fields, electroretinogram, and dark-adapted thresholds than did three younger affected relatives, ranging in age from 22 to 38 years. Conclusion: An early onset, blinding form of autosomal dominant RP results from a rhodopsin Cys187Tyr mutation that eliminates a residue necessary for the formation of a highly conserved disulfide bond essential to normal rhodopsin function. The fact that one family member is significantly less affected than his younger relatives suggests that genetic or environmental factors can modulate the phenotype.
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