RETINAL DEGENERATIONS WITH TRUNCATION MUTATIONS IN THE CONE-ROD HOMEOBOX (CRX) GENE

PURPOSE. To define the phenotypes of retinal degenerations associated with mutations in the gene encoding CRX (cone-rod homeobox), a photore ceptor-specific transcription factor. METHODS. Heterozygotes with the E168 [Delta 1 bp], E168 [Delta 2 bp], or G217 [Delta 1 bp] CRX gene mu tation were studied clinically, with visual function tests, including rod and cone perimetry and electroretinography (ERG), and with optical coherence tomography (OCT). RESULTS. Clinical diagnoses included auto somal dominant cone-rod dystrophy in one family (E168 [Delta 1 bp] mut ation) and simplex Leber congenital amaurosis in two families (E168 [D elta 2 bp], G217 [Delta 1 bp] mutations). In the family with the E168 [Delta 1 bp] mutation, two siblings had relatively mild disease expres sion in the third decade of life. The central retinas of these two pat ients had profound loss of rod and shea wavelength cone function; long /middle wavelength cone thresholds were elevated at fixation, but ther e were greater paracentral than central abnormalities. Peripheral reti nal dysfunction was evident by psychophysics and by maximum amplitude loss for rod- and cane-isolated ERG photoreceptor responses. OCT cross -sectional reflectance images showed decreased central retinal thickne ss consistent with photoreceptor loss. An additional member of this fa mily (E168 [Delta 1 bp] mutation) and two other patients (representing E168 [Delta 2 bp] and G217 [Delta 1 bp] mutations) had a severe pheno type with retina-wide loss of function and islands of function remaini ng only in the temporal periphery. CONCLUSIONS. Truncation mutations i n CRX are associated with retinopathies that share phenotypic features but vary in disease severity. The disease mechanism could involve abn ormal photoreceptor development compounded by a disturbance in the mai ntenance of photoreceptors in the mature retina.