Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene () Essential for Maintenance of the Photoreceptor

TLDR

Inherited retinal degeneration genes encode proteins essential for phototransduction, metabolism, or structural support of photoreceptors. The study demonstrates that autosomal‑dominant cone‑rod dystrophy at the CORD2 locus on chromosome 19q13 results from mutations in a novel photoreceptor‑specific homeodomain transcription factor, CRX. Mutations such as E80A and a 1‑bp deletion truncating the C‑terminal 132 residues of CRX cause adCRD through haploinsufficiency or dominant‑negative effects, confirming CRX’s essential role in photoreceptor maintenance.

Abstract

Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A). In another CRD family, a 1 bp deletion (E168 [Δ1 bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptors.