Leber congenital amaurosis (LCA) is the most severe retinal dystrophy causing blindness or severe visual impairment before the age of 1 year. Linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 14 genes mutated in patients with LCA and juvenile retinal degeneration, which together explain approximately 70% of the cases. Several of these genes have also been implicated in other non-syndromic or syndromic retinal diseases, such as retinitis pigmentosa and Joubert syndrome, respectively. CEP290 (15%), GUCY2D (12%), and CRB1 (10%) are the most frequently mutated LCA genes; one intronic CEP290 mutation (p.Cys998X) is found in approximately 20% of all LCA patients from north-western Europe, although this frequency is lower in other populations. Despite the large degree of genetic and allelic heterogeneity, it is possible to identify the causative mutations in approximately 55% of LCA patients by employing a microarray-based, allele-specific primer extension analysis of all known DNA variants. The LCA genes encode proteins with a wide variety of retinal functions, such as photoreceptor morphogenesis (CRB1, CRX), phototransduction (AIPL1, GUCY2D), vitamin A cycling (LRAT, RDH12, RPE65), guanine synthesis (IMPDH1), and outer segment phagocytosis (MERTK). Recently, several defects were identified that are likely to affect intra-photoreceptor ciliary transport processes (CEP290, LCA5, RPGRIP1, TULP1). As the eye represents an accessible and immune-privileged organ, it appears to be uniquely suitable for human gene replacement therapy. Rodent (Crb1, Lrat, Mertk, Rpe65, Rpgrip1), avian (Gucy2D) and canine (Rpe65) models for LCA and profound visual impairment have been successfully corrected employing adeno-associated virus or lentivirus-based gene therapy. Moreover, phase 1 clinical trials have been carried out in humans with RPE65 deficiencies. Apart from ethical considerations inherently linked to treating children, major obstacles for the treatment of LCA could be the putative developmental deficiencies in the visual cortex in persons blind from birth (amblyopia), the absence of sufficient numbers of viable photoreceptor or RPE cells in LCA patients, and the unknown and possibly toxic effects of overexpression of transduced genes. Future LCA research will focus on the identification of the remaining causal genes, the elucidation of the molecular mechanisms of disease in the retina, and the development of gene therapy approaches for different genetic subtypes of LCA.

中文翻译：

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莱伯先天性黑ama症：基因，蛋白质和疾病机制。

莱伯先天性黑蒙（LCA）是最严重的视网膜营养不良，在1岁之前会导致失明或严重的视力障碍。连锁分析，纯合性作图和候选基因分析促进了LCA和青少年视网膜变性患者中14个突变基因的鉴定，这共同解释了大约70％的病例。这些基因中的几种还分别与其他非综合征或综合征性视网膜疾病有关，例如色素性视网膜炎和Joubert综合征。CEP290（15％），GUCY2D（12％）和CRB1（10％）是突变频率最高的LCA基因；在欧洲西北部的所有LCA患者中，大约有20％发现了一个内含子CEP290突变（p.Cys998X），尽管在其他人群中此频率较低。尽管遗传和等位基因异质性很大，通过对所有已知DNA变体进行基于微阵列的等位基因特异性引物延伸分析，可以鉴定大约55％的LCA患者的致病突变。LCA基因编码具有多种视网膜功能的蛋白质，例如光感受器形态发生（CRB1，CRX），光转导（AIPL1，GUCY2D），维生素A循环（LRAT，RDH12，RPE65），鸟嘌呤合成（IMPDH1）和外部片段吞噬作用（MERTK）。最近，发现了一些可能影响感光器内睫状体转运过程的缺陷（CEP290，LCA5，RPGRIP1，TULP1）。由于眼睛代表易于接近且具有免疫功能的器官，因此它似乎特别适合于人类基因替代疗法。啮齿动物（Crb1，Lrat，Mertk，Rpe65，Rpgrip1），使用腺相关病毒或慢病毒的基因治疗已成功纠正了LCA和严重视力障碍的禽类（Gucy2D）和犬类（Rpe65）模型。此外，已经在具有RPE65缺陷的人类中进行了1期临床试验。除了与治疗儿童固有的道德考虑外，治疗LCA的主要障碍可能是出生盲人（弱视）的视皮层假定的发育缺陷，LCA患者缺乏足够数量的存活感光细胞或RPE细胞，以及转导基因过表达的未知和可能的毒性作用。未来的LCA研究将着重于确定剩余的因果基因，阐明视网膜疾病的分子机制，