CONE-ROD DYSTROPHY DUE TO MUTATIONS IN A NOVEL PHOTORECEPTOR-SPECIFICHOMEOBOX GENE (CRX) ESSENTIAL FOR MAINTENANCE OF THE PHOTORECEPTOR

Genes associated with inherited retinal degeneration have been found t o encode proteins required for phototransduction, metabolism, or struc tural support of photoreceptors. Here we show that mutations in a nove l photoreceptor-specific homeodomain transcription factor gene (CRX) c ause an autosomal dominant form of cone-rod dystrophy (adCRD) at the C ORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of th e recognition helix is replaced by alanine (E80A). In another CRD fami ly, a 1 bp deletion (E168 [Delta bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mut ations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for t he maintenance of mammalian photoreceptors.