Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1
Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1
复制标题
DOI：
10.1093/hmg/9.20.3011
复制
发表时间：
2000-12-12
影响因子：
3.5
通讯作者：
Schiaffino, MV
中科院分区：
文献类型：
--
作者：
d'Addio, M;Pizzigoni, A;Schiaffino, MV
眼白化病1型（OA 1）是一种X-连锁疾病，主要特征是视力严重下降、视网膜色素减退以及皮肤和眼睛中存在大黑素体。在患有该疾病的患者中，已经鉴定出OA 1基因内的各种类型的突变，包括几种功能意义未知的错义突变。为了阐明眼白化病的分子发病机制，并可能定义关键的功能结构域内的OA 1蛋白，我们的特点是19个独立的错义突变相对于加工和亚细胞分布在COS-7细胞中的表达。我们的分析表明，存在至少两个不同的生物化学缺陷与不同的错义突变，19个OA 1突变体中的11个（类似于60%）保留在内质网中，显示出缺陷的细胞内转运和糖基化，与蛋白质错误折叠一致。19个OA 1突变体中的其余8个（类似于40%）显示与野生型蛋白质的分选和加工行为没有区别。与我们最近的研究结果一致，OA 1代表一种新型的细胞内G蛋白偶联受体（GPCR），我们发现大多数这些后者的突变簇在第二和第三胞质环，两个区域，在典型的GPCR是已知的是关键的下游信号，包括G蛋白偶联和效应激活。在这项研究中进行的OA 1突变的生化分析提供了重要的见解OA 1蛋白的结构-功能关系，并意味着蛋白质错误折叠的主要致病机制OA 1。
Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by a severe reduction of visual acuity, hypopigmentation of the retina and the presence of macromelanosomes in the skin and eyes, Various types of mutation have been identified within the OA1 gene in patients with the disorder, including several missense mutations of unknown functional significance. In order to shed light into the molecular pathogenesis of ocular albinism and possibly define critical functional domains within the OA1 protein, we characterized 19 independent missense mutations with respect to processing and subcellular distribution on expression in COS-7 cells. Our analysis indicates the presence of at least two distinct biochemical defects associated with the different missense mutations, Eleven of the nineteen OA1 mutants (similar to 60%) were retained in the endoplasmic reticulum, showing defecNStive intracellular transport and glycosylation, consistent with protein misfolding. The remaining eight of the nineteen OA1 mutants (similar to 40%) displayed sorting and processing behaviours indistinguishable from those of the wild-type protein. Consistent with our recent findings that OA1 represents a novel type of intracellular G protein-coupled receptor (GPCR), we found that most of these latter mutations cluster within the second and third cytosolic loops, two regions that in canonical GPCRs are known to be critical for their downstream signaling, including G protein-coupling and effector activation. The biochemical analysis of OA1 mutations performed in this study provides important insights into the structure-function relationships of the OA1 protein and implies protein misfolding as a major pathogenic mechanism in OA1.