Roma Cristin, Ferrante Paola, Guardiola Ombretta, Ballabio Andrea, Zollo Massimo
CEINGE-Biotecnologie Avanzate, Naples, Italy.
Gene. 2007 Nov 1;402(1-2):20-7. doi: 10.1016/j.gene.2007.07.020. Epub 2007 Aug 1.
As the most common form of ocular albinism, ocular albinism type I (OA1) is an X-linked disorder that has an estimated prevalence of about 1:50,000. We searched for mutations through the human genome sequence draft by direct sequencing on eighteen patients with OA1, both within the coding region and in a thousand base pairs upstream of its start site. Here, we have identified eight new mutations located in the coding region of the gene. Two independent mutations, both located in the most carboxyterminal protein regions, were further characterized by immunofluorescence confocal microscopy, thus showing an impairment in their subcellular distribution into the lysosomal compartment of Cos-7A cells. The mutations found can result in protein misfolding, thus underlining the importance of the structure-function relationships of the protein as a major pathogenic mechanism in ocular albinism. Seven individuals out of eighteen (38.9%) with a clinical diagnosis of ocular albinism showed mutations, thus underlining the discrepancies between the clinical phenotype features and their genotype correlations. We postulate that mutations that have not yet been identified are potentially located in non-coding conserved regions or regulatory sequences of the OA1 gene.
作为眼部白化病最常见的形式，I型眼部白化病（OA1）是一种X连锁疾病，估计患病率约为1:50,000。我们通过直接测序在18例OA1患者的人类基因组序列草图中搜索突变，包括编码区域及其起始位点上游一千个碱基对的区域。在此，我们在该基因的编码区域中鉴定出八个新突变。两个独立的突变均位于最羧基末端的蛋白质区域，通过免疫荧光共聚焦显微镜进一步表征，结果显示它们在亚细胞水平向Cos - 7A细胞溶酶体区室的分布受损。发现的这些突变可导致蛋白质错误折叠，从而突出了蛋白质结构 - 功能关系作为眼部白化病主要致病机制的重要性。18例临床诊断为眼部白化病的患者中有7例（38.9%）显示出突变，这凸显了临床表型特征与其基因型相关性之间的差异。我们推测尚未鉴定出的突变可能位于OA1基因的非编码保守区域或调控序列中。
