den Hollander Anneke I, McGee Terri L, Ziviello Carmela, Banfi Sandro, Dryja Thaddeus P, Gonzalez-Fernandez Federico, Ghosh Debashis, Berson Eliot L
Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Massachusetts 02114, USA.
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1864-72. doi: 10.1167/iovs.08-2497. Epub 2008 Dec 13.
Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP gene (RBP3) are associated with photoreceptor degeneration.
A consanguineous family was ascertained in which four children had autosomal recessive retinitis pigmentosa (RP). Homozygosity mapping performed with SNP microarrays revealed only one homozygous region shared by all four affected siblings. Sequencing of RBP3, contained in this region, was performed in this family and others with recessive RP. Screening was also performed on patients with various other forms of retinal degeneration or malfunction.
Sequence analysis of RBP3 revealed a homozygous missense mutation (p.Asp1080Asn) in the four affected siblings. The mutation affects a residue that is completely conserved in all four homologous modules of the IRBP protein of vertebrate species and in C-terminal-processing proteases, photosynthesis enzymes found in bacteria, algae, and plants. Based on the previously reported crystal structure of Xenopus IRBP, the authors predict that the Asp1080-mediated conserved salt bridge that appears to participate in scaffolding of the retinol-binding domain is abolished by the mutation. No RBP3 mutations were detected in 395 unrelated patients with recessive or isolate RP or in 680 patients with other forms of hereditary retinal degeneration.
Mutations in RBP3 are an infrequent cause of autosomal recessive RP. The mutation Asp1080Asn may alter the conformation of the IRBP protein by disrupting a conserved salt bridge.
光感受器间类视黄醇结合蛋白（IRBP）被认为对正常的视杆和视锥功能至关重要，因为它介导类视黄醇在光感受器和视网膜色素上皮之间的转运。本研究旨在确定IRBP基因（RBP3）的突变是否与光感受器变性相关。
确定了一个近亲家庭，其中四个孩子患有常染色体隐性遗传性视网膜色素变性（RP）。使用单核苷酸多态性微阵列进行纯合性定位，结果显示所有四个受影响的兄弟姐妹仅共享一个纯合区域。对该区域包含的RBP3进行测序，并在这个家庭以及其他患有隐性RP的家庭中进行。还对患有各种其他形式视网膜变性或功能障碍的患者进行了筛查。
RBP3的序列分析显示，四个受影响的兄弟姐妹中存在纯合错义突变（p.Asp1080Asn）。该突变影响一个在脊椎动物物种IRBP蛋白的所有四个同源模块以及C末端加工蛋白酶（细菌、藻类和植物中发现的光合作用酶）中完全保守的残基。基于先前报道的非洲爪蟾IRBP的晶体结构，作者预测该突变消除了似乎参与视黄醇结合域支架构建的Asp1080介导的保守盐桥。在395名患有隐性或散发性RP的无关患者以及680名患有其他形式遗传性视网膜变性的患者中未检测到RBP3突变。
RBP3突变是常染色体隐性RP的罕见病因。Asp1080Asn突变可能通过破坏保守盐桥改变IRBP蛋白的构象。
