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 photoreceptor- specific transcription factor. METHODS. Heterozygotes with the E168 [Δ1 bp], E168 [Δ2 bp], or G217 [Δ1 bp] CRX gene mutation 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 autosomal dominant cone-rod dystrophy in one family (E168 [Δ1 bp] mutation) and simplex Leber congenital amaurosis in two families (E168 [Δ2 bp], G217 [Δ1 bp] mutations). In the family with the E168 [Δ1 bp] mutation, two siblings had relatively mild disease expression in the third decade of life. The central retinas of these two patients had profound loss of rod and short wavelength cone function; long/middle wavelength cone thresholds were elevated at fixation, but there were greater paracentral than central abnormalities. Peripheral retinal dysfunction was evident by psychophysics and by maximum amplitude loss for rod- and cone- isolated ERG photoreceptor responses. OCT cross-sectional reflectance images showed decreased central retinal thickness consistent with photoreceptor loss. An additional member of this family (E168 [Δ1 bp] mutation) and two other patients (representing E168 [Δ2 bp] and G217 [Δ1 bp] mutations) had a severe phenotype with retina-wide loss of function and islands of function remaining only in the temporal periphery. CONCLUSIONS. Truncation mutations in CRX are associated with retinopathies that share phenotypic features but vary in disease severity. The disease mechanism could involve abnormal photoreceptor development compounded by a disturbance in the maintenance of photoreceptors in the mature retina.