This report describes the clinical course and visual prognosis in two families with cone dystrophy due to RPGR mutations in the 3' terminal region of ORF15.
We mapped two families with X-linked cone dystrophy to the COD1 locus and identified two distinct mutations in ORF15 in the RPGR gene (ORF15+1343_1344delGG and ORF15+694_708del15) leading to a frame-shift and premature termination of translation in one case and a deletion of five amino acids in another.
CSNB4 is not allelic with any previously reported XLRP loci; however, the interval overlaps the locus reported to contain the cone dystrophy (COD1) gene, and both diseases are nonrecombinant with DXS993.
So far, CNGA3 mutations are not only one of the most common causes of achromatopsia and cone dystrophy or cone-rod dystrophy but also one of the most commonly mutated genes among various forms of retinopathy.
As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice.
These findings open new avenues of research to explore the biological role of the LE in the biosynthetic pathway and the etiology of cone dystrophy caused by PRPH2 mutations and/or malfunctions of the LE.<b>SIGNIFICANCE STATEMENT</b> Peripherin 2 (PRPH2) is a tetraspanin protein abundantly expressed in the light-sensing cilium, the outer segment, of the vertebrate photoreceptor.
We adopted this strategy to mimic the phenotype diversity encounter in humans and generate a cohort of pigs for cone dystrophy by expressing a dominant mutant allele of the guanylate cyclase 2D (GUCY2D) gene.
We found a heterozygous G to C substitution in the 5' untranslated region (UTR) of the PDE6H gene in the DNA of a patient with a distinctive form of cone dystrophy, her sibling, and their father.
Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.
Protein-NP interactions were thoroughly investigated for the wild type (WT) GCAP1 as well as for a variant carrying the Asp 100 to Glu mutation (D100E), which prevents the binding of Ca<sup>2+</sup> to the highest affinity site and is linked to cone dystrophy.
GUCA1Ap.D100E, another mutation previously implicated in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative effect.