GENOTYPE & PHENOTYPE IN LEBER CONGENITAL AMAUROSIS & RELATED RETINAL DISORDERS

这是一项试验性研究，旨在研究Leber先天性黑色素沉着症、早发性视网膜色素沉着症(RP)和视锥-杆营养不良(CRD)的三个疾病基因，以及这些基因控制人类视网膜功能的可能性，这些基因可以通过适当的测试进行评估。这三个基因分别是CRX，它参与视蛋白的表达和光感受器的分化；在光感受器中表达；RetGC，视网膜鸟苷酸环化酶；也在光感受器中表达；RPE65，在视网膜色素上皮中表达，可能是视觉周期中的异构酶。CRX基因突变预计会导致视蛋白表达不足，继而导致视觉色素视紫红质缺陷、光感受器外节缩短、光电流低、光感受器和视觉敏感度下降，这些都与存在的视觉色素的数量成正比。这些预测可以通过视网膜电信号和心理物理程序的组合来检验，例如在暗适应期间测量阈值。RetGC的蛋白是鸟苷酸环化酶。光感受器外节中的循环GMP通道在黑暗中开放，并在光响应时关闭。环化酶可重新合成cGMP。研究人员预测，循环酶的异常将改变光感受器光电流恢复的动力学，从而改变视网膜适应，即对光明和黑暗的适应。这可以通过对暗适应的研究和对光感受器对光的反应恢复动力学的ERG评估来检验。RPE65在色素上皮细胞中表达，并参与维甲酸的代谢。这种蛋白质可能就是视觉周期中的异构酶。这种酶将所有反式视黄醛转化为11顺式视黄醛，视黄醛与视黄素结合，在感光细胞外节形成视觉色素。视觉色素捕捉光线，开始产生视觉的过程。研究人员假设，RPE65通过异构酶(或密切相关的酶)的变化，改变了光感受器感光敏感度和视觉敏感度在暴露于光后恢复的动力学。这一预测可以通过使用视网膜电信号和心理物理程序的视力和视网膜功能测试的组合来检验。上述假设将在LCA和相关条件下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，这限制了对他们的假设进行验证的可能性。

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.