GENOTYPE & PHENOTYPE IN LEBER CONGENITAL AMAUROSIS & RELATED RETINAL DISORDERS

这是一项针对Leber先天性黑蒙、早发性视网膜色素变性（RP）和视锥-视杆细胞营养不良（CRD）的三种疾病基因的初步研究，以及这些基因控制人类视网膜功能的可能性，这些功能可以通过适当的测试进行评估。这三个基因是CRX，其参与视蛋白表达和感光细胞分化;在感光细胞中表达; RetGC，视网膜鸟苷酸环化酶;也在感光细胞中表达; RPE 65，在视网膜色素上皮中表达，可能是视觉周期中的异构酶。预测CRX的突变引起视蛋白表达缺陷，随之而来的是视色素视紫红质的缺陷、光感受器外段的缩短、低光电流、光感受器和视觉灵敏度的降低，其与存在的视色素的量成比例。这些预测可以用视网膜电图和心理物理程序的组合来测试，例如暗适应期间的阈值测量。RetGC的蛋白质是鸟苷酸环化酶。光感受器外节中的环GMP通道在黑暗中打开，并响应于光而关闭。环化酶再合成cGMP。研究人员预测，环化酶的异常将改变光感受器光电流的恢复动力学，从而改变视网膜适应，即对光和暗的调整。这可以通过研究暗适应和ERG评估光感受器对光的响应的恢复动力学来测试。RPE 65在色素上皮中表达，并且参与类维生素A的代谢。这种蛋白质可能是视觉循环中的异构酶。这种酶将全反式转化为11-顺式形式的丙醛，该丙醛与视蛋白结合以形成感光器外节中的视觉色素。视觉色素捕捉光线并启动导致视觉的过程。研究人员假设RPE 65通过异构酶（或密切相关的酶）的改变，改变了光感受器的敏感性和暴露于光后的视觉敏感性的恢复动力学。这种预测可以通过使用采用视网膜电图和心理物理程序的视觉和视网膜功能测试的组合来测试。上述假设将在LCA和相关疾病的专性杂合子个体中进行检验。这些人是受影响儿童的父母。受影响的儿童有严重的视力障碍和眼球震颤，这限制了在他们身上检验假设的可能性。

This is a pilot study looking at three disease genes for Leber Congenital Amaurosis, early onset Retinitis Pigmentosia (RP) and Cone-Rod Dystrophy (CRD), and the likelihood that these genes govern human retinal functions that can be evaluated by appropriate tests. The three genes are CRX, which is involved in opsin expression and photoreceptor differentiation; expressed in the photoreceptor; RetGC, Retinal Guanylyl Cyclase; also expressed in the photoreceptors; RPE65, expressed in the retinal pigment epithelium, possibly the isomerase in the visual cycle. Mutations of CRX are predicted to cause deficient opsin expression with consequent deficiencies in the visual pigment rhodopsin, shortening of the photorecptor outer segments, low photocurrent, reductions in the photoreceptor and visual sensitivity that are proportional to the amount of the visual pigment present. These predictions can be tested with a combination of electroretinographic and psychophysical procedures, such as measurements of threshold during dark adaptation. The protein of RetGC is guanylyl cyclase. Cyclic GMP channels in the photoreceptor outer segments are open in the dark, and close in response to light. The cyclase resynthesizes cGMP. The investigators predict abnormalities in the cyclase will alter the kinetics of recovery of the photoreceptors' photocurrent with consequent alterations in retinal adaptation, that is the adjustment to light and dark. This can be tested by studies of dark adaptation and ERG assessment of the kinetics of recovery of the photoreceptors' response to light. RPE65 is expressed in the pigment epithelium, and is involved in metabolism of retinoids. Possibly the protein is the isomerase in the visual cycle. This enzyme converts all trans to the 11-cis form of retinaldehyde which is bound to opsin to form the visual pigment in the photoreceptor outer segments. The visual pigment catches light and starts the processes that result in vision. The investigators hypothesize that RPE65, by alterations in isomerase (or closely related enzymes), alter the kinetics of recovery of the photoreceptor's sensitivity and visual sensitivity after exposure to light. This prediction can be tested by using a combination of tests of vision and retinal function that employ electroretinographic and psychophysical procedures. The above hypotheses will be tested in individuals who are obligate heterozygotes for LCA and the related conditions. These individuals are the parents of affected children. The affected children have severe visual impairment and nystagmus which limits the possibility of testing the hypotheses in them.