title: 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.
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand. marion.maw@stonebow.otago.ac.nz
authors.forename: M A
authors.initials: MA
authors.lastname: Maw
authors.forename: B
authors.initials: B
authors.lastname: Kennedy
authors.forename: A
authors.initials: A
authors.lastname: Knight
authors.forename: R
authors.initials: R
authors.lastname: Bridges
authors.forename: K E
authors.initials: KE
authors.lastname: Roth
authors.forename: E J
authors.initials: EJ
authors.lastname: Mani
authors.forename: J K
authors.initials: JK
authors.lastname: Mukkadan
authors.forename: D
authors.initials: D
authors.lastname: Nancarrow
authors.forename: J W
authors.initials: JW
authors.lastname: Crabb
authors.forename: M J
authors.initials: MJ
authors.lastname: Denton
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D003241:Consanguinity; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012172:Retinaldehyde / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: C020932:11-cis-retinal-binding protein; D002352:Carrier Proteins; D017931:DNA Primers; D011994:Recombinant Proteins; D012172:Retinaldehyde