Nature Genetics
17, 198 - 200 (1997)
doi:10.1038/ng1097-198
Mutation of the gene encoding cellular retinaldehyde−binding protein in autosomal recessive retinitis pigmentosaMarion A. Maw1, 5, Breandan Kennedy2, Allison Knight1, Robyn Bridges1, Karen E. Roth2, E.J. Mani3, J.K. Mukkadan3, Derek Nancarrow4, John W. Crabb2
& Michael J. Denton1
1Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand.
2Protein Chemistry Facility, W.Alton Jones Cell Science Center, 10 Old Barn Road, Lake Placid, New York 12946, USA.
3Little Flower Medical Research Centre, Angamally 683 572, Kerala, India.
4Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Brisbane, Australia.
5e-mail: marion.maw@stonebow.otago.ac.nz. 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 degenerations1,2. 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-retinaldehyde3−5. 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.
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