The Phenotypes of Patients and Heterozygous Carriers With RDH12 Mutations Are Different From Those With RPE65 Mutations

Abstract

Abstract: : Purpose: Mutations in 2 genes encoding proteins of the retinoid cycle are associated with Leber congenital amaurosis and a form of juvenile onset retinitis pigmentosa (RP). RPE65 is expressed in the retinal pigment epithelium (RPE) and defects lead to an inability to recover 11–cis retinal, accumulation of all trans retinyl esters and cell death via light–independent signaling of constitutively activated rhodopsin, unbound to 11–cis retinal. RDH12, however, is expressed in the photoreceptors and encodes a retinol dehydrogenase involved in the conversion of all trans retinal to all trans retinol. In an attempt to better understand the disease process, we are studying the consequences of heterozygous LCA mutations in the carrier state. We tested the hypotheses that RDH12 heterozygotes have a phenotype distinguishable from that of the RPE65 defect. Methods: Mutation screening is by LCA microarray (Asper), dHPLC wave analysis (Transgenomics), and automated sequencing (ABI, Perkin Elmer). Indirect ophthalmoscopy, slit lamp biomicroscopy, electroretinography (ERG), multifocal ERGs (mfERG), and photopic hill analysis were performed. Results: A patient with a novel homozygous p.C285Y RDH12 mutation presented at age 5 with 20/200 OD and 20/30 OS. Nystagmus was found in the OD only. Goldmann visual fields (VF) were 10° OD and 40° OS (V4e target). A diffuse atrophy of the RPE, and pigmentary maculopathy were noted. Nondetectable rod responses and 3µV cone b–waves were found at age 5, while the ERG was nondetectable and the VF was 5° OU at age 7. Heterozygous carriers had significant cone ERG abnormalities, abnormal photopic hills and subtle retinal abnormalities. Conclusions: The C258Y RDH12 change is a novel loss–of–function mutation. Obligate carriers of this mutation have subclinical disease of the cone photoreceptor pathway, while the affected has a rapidly progressive retinal dystrophy with a maculopathy. Functional testing of RDH12 heterozygotes provides important physiological information of the retinal dystrophy in the offspring with juv RP. Also, these relatively simple clinical tests on the parents suggest the molecular defect in blind children and fascilitates subsequent molecular diagnostic testing.

Keywords: retinal degenerations: hereditary • gene/expression • photoreceptors