Autosomal dominant retinal degeneration and bone loss in patients with a 12-bp deletion in the CRX gene

PURPOSE. To define the phenotypic expression of a deletion in the gene enco ding the transcription factor CRX in a large, seven-generation, white famil y. METHODS. Fourteen affected individuals, all heterozygous for the Leu146del1 2 mutation in the cone-rod homeobox gene (CRX), and four nonaffected relati ves from the same family were examined with visual function tests, and 10 u nderwent bone mineral density (BMD) measurement. RESULTS. The ability of the mutated CRX protein to transactivate rhodopsin promoter was decreased by approximately 25%, and its ability to react syner gistically with neural retinal leucine zipper (NRL) was reduced by more tha n 30%. The affected members of the family had an autosomal dominant ocular condition most closely resembling Leber congenital amaurosis (LCA) with sev ere visual impairment at an early age. Depending on age, affected members s howed varying degrees of significant visual acuity loss, elevated dark-adap tation thresholds, significantly reduced cone and rod electroretinogram (ER G) amplitudes, and progressive constriction of the visual fields, in most c ases leading to complete blindness. Six affected members had reduced levels of BMD in the spine and the hdp (osteopenia). Four affected female members who were receiving long-term hormonal replacement therapy (HRT) demonstrat ed normal values of BMD. CONCLUSIONS. This large deletion of the CRX gene is associated with a sever e form of autosomal dominant retinal degeneration. Affected members not rec eiving HRT showed reduced BMD (osteopenia). This phenotype may reflect the abnormal influence of mutant CRX on both retinal and pineal development.