Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa
Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa
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DOI：
10.1038/ng1097-198
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发表时间：
1997-10-01
期刊：
影响因子：
30.8
通讯作者：
Denton, MJ
中科院分区：
文献类型：
--
作者：
Maw, MA;Kennedy, B;Denton, MJ
血液中全反式视黄醇水平不足会导致视网膜功能障碍；因此，与视网膜维生素A代谢有关的基因是遗传性视网膜变性的候选基因(1，2)。在本研究中，对一个分离非综合征型常染色体隐性视网膜色素变性(Arrp)血缘关系的家系进行的分子遗传学分析表明，患者的兄弟姐妹是纯合子，RLBP1是编码细胞视黄醛结合蛋白(CRALBP)的基因。这种取代预计将在残基150位用谷氨酰胺取代精氨酸。CRALBP在光感受器中不表达，但在视网膜色素上皮(RPE)和神经视网膜的Muller细胞中大量表达，它携带11-顺式视黄醇和11-顺式视黄醛(3-5)。当在细菌中表达时，含有R150Q取代的重组CRALBP(RCRALBP)的可溶性低于野生型rCRALBP。从可溶性细胞裂解液中纯化了突变体rCRALBP，并用质谱仪对其结构进行了验证。突变蛋白缺乏结合11-顺式视黄醛的能力。这些发现表明，目前家系中的arrp是由于缺乏功能性CRALBP，可能导致视网膜维生素A代谢中断。
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(1,2). 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 Muller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde(3-5). 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 of 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.