Effects of deficiency in the RLBP1-encoded visual cycle protein CRALBP on visual dysfunction in humans and mice

Jose Ronaldo Lima De Carvalho,Hye Jin Kim,Keiko Ueda,Jin Zhao,Aaron P Owji,Tingting Yang,Stephen H Tsang,Janet R Sparrow

doi:10.1074/jbc.ra120.012695

Abstract

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

Highlights

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration
Mutations in retinaldehyde-binding protein 1 (RLBP1), the gene encoding CRALBP, cause autosomal recessive retinal diseases with phenotypes described as retinitis punctata albescens (RPA), autosomal recessive retinitis pigmentosa, Bothnia dystrophy, and Newfoundland rod-cone dystrophy [2,3,4,5,6,7,8,9]
We have presented the clinical and molecular analyses of two siblings compound heterozygous for disease-causing mutations in the RLBP1 gene, their carrier parents, and CralbpϪ/Ϫ mice

Summary

Introduction

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. Delayed dark adaptation is exhibited by human patients carrying a mutation of the RLBP1/ CRALBP gene and by CralbpϪ/Ϫ mice [1, 2, 9]. Unreported features of RLBP1/CRALBP disease in the affected patients are presented and replication in CralbpϪ/Ϫ mice is demonstrated.

Results

Conclusion