GENOTYPE & PHENOTYPE IN LEBER CONGENITAL AMAUROSIS & RELATED RETINAL DISORDERS

基因型

• 批准号: 6441967
• 负责人: ANNE B FULTON
• 金额: $ 2.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6441967
• 关键词: blindness; clinical research; dark adaptation; densitometry; disease /disorder onset; electroretinography; family genetics; gene mutation; genotype; guanylate cyclase; human subject; phenotype; retinal pigment epithelium; retinitis pigmentosa; rhodopsin; rod cell; sensory mechanism; visual photoreceptor

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.

这是一项初步研究，着眼于莱伯先天性黑蒙、早发性视网膜色素变性（RP）和视锥细胞营养不良（CRD）的三种疾病基因，以及这些基因控制人类视网膜功能的可能性，可以通过适当的测试进行评估。这三个基因分别是CRX，参与视蛋白表达和光感受器分化；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，可能是视觉循环中的异构酶。预计 CRX 突变会导致视蛋白表达缺陷，从而导致视色素视紫红质缺陷、感光器外节缩短、光电流降低、光感受器和视觉敏感度降低（与视色素存在量成正比）。这些预测可以通过结合视网膜电图和心理物理学程序来测试，例如暗适应过程中阈值的测量。 RetGC的蛋白质是鸟苷酸环化酶。光感受器外节中的环状 GMP 通道在黑暗中打开，并在光线响应时关闭。环化酶重新合成 cGMP。研究人员预测环化酶的异常将改变光感受器光电流恢复的动力学，从而改变视网膜适应，即对光和暗的调整。这可以通过暗适应研究和光感受器光响应恢复动力学的 ERG 评估来测试。 RPE65 在色素上皮中表达，并参与类视黄醇的代谢。该蛋白质可能是视觉循环中的异构酶。这种酶将所有反式视黄醛转化为 11-顺式视黄醛，视黄醛与视蛋白结合，在感光器外节中形成视色素。视觉色素捕捉光线并启动产生视觉的过程。研究人员推测，RPE65 通过异构酶（或密切相关的酶）的改变，改变暴露于光后感光器敏感性和视觉敏感性恢复的动力学。这种预测可以通过结合使用视网膜电图和心理物理程序的视力和视网膜功能测试来进行测试。上述假设将在 LCA 和相关病症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，这限制了测试他们的假设的可能性。