Mutation of the gene encoding cellular retinaldehyde–binding protein in autosomal recessive retinitis pigmentosa

Abstract

Inadequate levels of all-trans-retinol in the blood cause retinal dysfunction; hence, genes implicated in retinal vitamin-A metabolism represent candidates for inherited retinal degenerations. In the current study, molecular genetic analysis of a consanguineous pedigree segregating for non-syndromic autosomal recessive retinitis pigmentosa (arRP) indicated that the affected siblings were homozygous by descent for a G4763A nucleotide substitution in RLBP1, the gene encoding cellular retinaldehyde-binding protein (CRALBP). This substitution is predicted to replace an arginine with glutamine at residue 150. CRALBP is not expressed in photoreceptors but is abundant in the retinal pigment epithelium (RPE) and Müller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. When expressed in bacteria, recombinant CRALBP (rCRALBP) containing the R150Q substitution was less soluble than wild-type rCRALBP. Mutant rCRALBP was purified from the soluble cell lysate and the protein structure was verified by mass spectrometry. The mutant protein lacked the ability to bind 11-cis-retinaldehyde. These findings suggest that arRP in the current pedigree results from a lack of functional CRALBP, presumably leading to disruption of retinal vitamin-A metabolism.

A novel compound heterozygous mutation in the cellular retinaldehyde-binding protein gene (RLBP1) in a patient with retinitis punctata albescens

“…However, the current published data are insufficient to infer a meaningful genotype-phenotype correlation. The phenotypic variability reported for the same mutations 1,4,5 suggests that other genetic or environmental factors may modify the clinical state. Identification of these novel mutations contribute to the structure-function studies that may guide future therapeutic efforts in these patients.…”

“…[1][2][3][4] The RLBP1-related retinopathies are characterized with subretinal punctate white-yellow deposits and clinical manifestations similar to that of RP. Fundus albipunctatus (FA) is an apparently stationary night blindness characterized by similar white-yellow deposits.…”

“…138, NO. 1ations. [1][2][3][4]7 Recombinant CRALBPs containing missense mutations have altered solubility or retinoid binding properties likely to disrupt the retinal vitamin-A metabolism.…”

“…[1][2][3][4]7 Recombinant CRALBPs containing missense mutations have altered solubility or retinoid binding properties likely to disrupt the retinal vitamin-A metabolism. 1,6 The 14-year-old boy presented with refractive error and denied having night blindness. There was no family history of RP.…”

The Retinal Pigment Epithelium Apical Microvilli and Retinal Function

“…3 Several forms of retinitis pigmentosa are known to be caused by mutations in visual-cycle protein genes such as RPE65, CRALBP, IRBP. 19,20 Macular edema resulting from pathologies such as uveitis, postoperative period following cataract extraction, 21 retinitis pigmentosa, 22 serpiginous choroiditis 23 and epiretinal membranes, 24 has been widely treated with carbonic anhydrase inhibitors. 25 Polarized distribution of carbonic anhydrase activity in the RPE apical surface has been reported.…”