Department of Ophthalmology, Columbia University Irving Medical Center, New York, New York 10032.
Department of Pharmacology, Columbia University Irving Medical Center, New York, New York 10032.
J Biol Chem. 2020 May 8;295(19):6767-6780. doi: 10.1074/jbc.RA120.012695. Epub 2020 Mar 18.
Mutations in (), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11--retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11--retinol oxidation to 11--retinal. CRALBP also maintains the 11- configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in /CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in /CRALBP carriers, and demonstrate consistencies between the affected individuals and /Cralbp mice. In the /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 /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--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 /Cralbp mice, reduced 11--retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.
突变 ()，编码视觉周期蛋白细胞视黄醛结合蛋白 (CRALBP)，导致常染色体隐性形式的视网膜变性。通过与 11--视黄醇结合，CRALBP 增强了视黄醇异构酶 RPE65（RPE65）的异构酶活性，并促进了 11--视黄醇向 11--视黄醛的氧化。CRALBP 还维持 11-构型并防止不必要的视醛活性。研究一对复合杂合突变的同胞对 /CRALBP，在这里我们扩展了受影响个体的表型，阐明了 /CRALBP 携带者中以前未报道的表型，并证明了受影响个体和 /Cralbp 小鼠之间的一致性。在 /CRALBP 受影响的个体中，经过长时间的暗适应后，可恢复不可记录的杆状特异性视网膜电图轨迹。在超广角眼底图像中，我们观察到典型的 /CRALBP 相关疾病呈放射状排列的斑点。光谱域光学相干断层扫描 (SD-OCT) 显示在光感受器相关带内存在高反射性畸变。在短波眼底自发荧光 (SW-AF) 图像中，斑驳的高自发荧光和斑驳表明黄斑受累。在受影响的个体及其无症状的携带父母中，SW-AF 强度降低，作为定量眼底自发荧光 (qAF) 测量，表明 11--视黄醛可用性的慢性损害，并提供了有关突变严重程度的信息。SD-OCT 信号向脉络膜的超传递以及近红外自发荧光 (NIR-AF) 的减少提供了视网膜色素上皮细胞 (RPE) 受累的证据。在 /Cralbp 小鼠中，11--视黄醇水平、qAF 和 NIR-AF 强度以及光感受器丧失的减少与受影响兄弟姐妹的临床表现一致。这些发现表明，突变与涉及 RPE 萎缩和光感受器细胞变性的进行性疾病有关。在无症状携带者中，qAF 揭示了以前未检测到的视觉周期缺陷。
