Lines Matthew A, Hébert Marc, McTaggart Kerry E, Flynn Sarah J, Tennant Matthew T, MacDonald Ian M
Department of Ophthalmology, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
Ophthalmology. 2002 Oct;109(10):1862-70. doi: 10.1016/s0161-6420(02)01187-9.
To reexamine a large Albertan family previously reported with a progressive cone dystrophy with variable phenotype and to map the disorder using molecular genetic techniques.
Observational case series.
Twenty-nine subjects (10 affected) from four generations of a large kindred were clinically examined. Twenty-three of these individuals, as well as two unaffected spouses, were included in the molecular genetic study. Subject ages ranged from 17 to 91 years of age.
Disease status and associated ocular abnormalities were assessed primarily by measurement of visual acuity, color vision, fundus photography, and both full-field and multifocal electroretinography (ERG and mfERG). Linkage of the disorder to the rhodopsin gene was studied using microsatellites. A mutational screen of the CRX gene was performed to identify coding sequence changes.
Visual acuity and color discrimination were reduced in clinically affected individuals; full-field flash ERG was used to measure function of both cones and rods. mfERG and fundus photography allowed documentation of the observed macular changes.
We noted a variable, adult-onset macular dystrophy, progressing in some cases to a retinitis pigmentosa-like phenotype. Both photopic and scotopic full-field ERG amplitudes were reduced by approximately 50%, demonstrating involvement of both photoreceptor systems. A reduced b-wave amplitude with a relatively preserved a-wave was observed at both cone and rod levels. Macular involvement was confirmed by mfERG. The rhodopsin locus was excluded by haplotype analysis. A novel frameshift mutation was detected in exon III of the CRX retinal homeobox gene. ERG and molecular genetic findings were consistent with the reclassification of this disease as an autosomal dominant cone-rod dystrophy (CRD) CONCLUSIONS: We report a novel CRX mutation causing autosomal dominant CRD. Observed ERG changes suggest that this mutation primarily impairs inner retinal function. Because retinal expression of CRX is limited to photoreceptors, this dysfunction may be the result of faulty photoreceptor communication with second-order retinal neurons. We propose misexpression of gated cation channels caused by altered CRX activity as one putative mechanism by which a sole photoreceptor defect may selectively impair neurotransmission without disrupting the upstream events of phototransduction.
重新研究一个先前报道的患有具有可变表型的进行性视锥细胞营养不良的艾伯塔大家族，并使用分子遗传学技术对该疾病进行定位。
观察性病例系列。
对来自一个大家族四代的29名受试者（10名患者）进行了临床检查。其中23名个体以及两名未受影响的配偶被纳入分子遗传学研究。受试者年龄在17至91岁之间。
主要通过测量视力、色觉、眼底照相以及全视野和多焦视网膜电图（ERG和mfERG）来评估疾病状态和相关的眼部异常。使用微卫星研究该疾病与视紫红质基因的连锁关系。对CRX基因进行突变筛查以识别编码序列变化。
临床受影响个体的视力和颜色辨别能力下降；全视野闪光ERG用于测量视锥细胞和视杆细胞的功能。mfERG和眼底照相可记录观察到的黄斑变化。
我们注意到一种可变的成人发病型黄斑营养不良，在某些情况下进展为色素性视网膜炎样表型。明视觉和暗视觉全视野ERG振幅均降低约50%，表明两个光感受器系统均受累。在视锥细胞和视杆细胞水平均观察到b波振幅降低而a波相对保留。mfERG证实了黄斑受累。通过单倍型分析排除了视紫红质基因座。在CRX视网膜同源框基因的外显子III中检测到一个新的移码突变。ERG和分子遗传学结果与将该疾病重新分类为常染色体显性视锥-视杆细胞营养不良（CRD）一致。
我们报告了一个导致常染色体显性CRD的新CRX突变。观察到的ERG变化表明该突变主要损害视网膜内层功能。由于CRX在视网膜中的表达仅限于光感受器，这种功能障碍可能是光感受器与二级视网膜神经元之间错误通信的结果。我们提出由CRX活性改变导致的门控阳离子通道错误表达是一种可能的机制，通过这种机制单一的光感受器缺陷可能选择性地损害神经传递而不干扰光转导的上游事件。
