生物谷报道：近日，荷兰遗传学家罗纳德·罗弗蒙和德国国立环境与健康研究中心的科学家合作，发现了一种控制视网膜疾病的基因LCA5，并且获得了这种基因是如何运行的证据。LCA5的发现是在失明研究领域里的一个重大进展，有望给眼盲的基因诊断与治疗带来新的机遇。
勒伯尔先天性黑蒙（LCA）是常染色体隐性视网膜营养不良导致的最为严重的疾病类型。通常在婴儿出生的几个月时间里导致失明。在不同的基因里，只通过一次单一的变异就能发病。加上新发现的LCA5基因，目前已经发现了10种LCA基因，这些基因与60%的眼病有关。德国国立环境与健康研究中心的马瑞斯博士说：“所有的这些基因缺失最后将导致同一症状，但是要针对不同的个体采取有效的治疗，必须知道发生变异的基因在哪一部位以及它会导致什么后果。”
研究者分析了LCA5基因对一种尚不完全清楚的蛋白质进行编码的过程，并研究了LCA5与其他在光学细胞运输中起作用的蛋白质是如何相互作用的。LCA5基因编码的蛋白在光感受器功能、视觉成像时转运视觉蛋白上起了重要的作用。如果LCA5的蛋白质合成受到干扰或破坏，视觉蛋白不能恰当地被转运到相应的外层部分，将导致光感受器停止工作并最终死亡，视觉功能就会丧失。
目前，LCA疾病本身还很难治愈。LCA基因治疗已经成功地应用到狗身上，因LCA缺陷而失明的狗经过治疗后，已恢复了视力。在伦敦一家大型医院里，十二名盲人已经开始接受基因临床治疗，并取得了令人振奋的结果。专家们表示，如果这些结果能经得起检验，有望在五到十年的时间里，将此方法应用于因LCA5基因缺陷而致盲的患者。（援引科技日报）
英文原文链接：
http://www.journalmed.de/newsview.php?id=18280
原始出处:
Nature Genetics 39, 889 - 895 (2007)
Published online: 3 June 2007 | doi:10.1038/ng2066
Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis
Anneke I den Hollander1,16, Robert K Koenekoop2,16, Moin D Mohamed3,4,16, Heleen H Arts1,16, Karsten Boldt5,6, Katherine V Towns3, Tina Sedmak7, Monika Beer5,6, Kerstin Nagel-Wolfrum7, Martin McKibbin3,8, Sharola Dharmaraj4, Irma Lopez2, Lenka Ivings3,9, Grange A Williams3, Kelly Springell3, C Geoff Woods10, Hussain Jafri11, Yasmin Rashid12, Tim M Strom5,6, Bert van der Zwaag13, Ilse Gosens1, Ferry F J Kersten1, Erwin van Wijk1, Joris A Veltman1, Marijke N Zonneveld1, Sylvia E C van Beersum1, Irene H Maumenee14, Uwe Wolfrum7, Michael E Cheetham15, Marius Ueffing5, Frans P M Cremers1,16, Chris F Inglehearn3,16 & Ronald Roepman1,16
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Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth. Here we show, using homozygosity mapping, that the LCA5 gene on chromosome 6q14, which encodes the previously unknown ciliary protein lebercilin, is associated with this disease. We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA. In a sixth family, the LCA5 transcript was completely absent. LCA5 is expressed widely throughout development, although the phenotype in affected individuals is limited to the eye. Lebercilin localizes to the connecting cilia of photoreceptors and to the microtubules, centrioles and primary cilia of cultured mammalian cells. Using tandem affinity purification, we identified 24 proteins that link lebercilin to centrosomal and ciliary functions. Members of this interactome represent candidate genes for LCA and other ciliopathies. Our findings emphasize the emerging role of disrupted ciliary processes in the molecular pathogenesis of LCA.
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
McGill Ocular Genetics Center, McGill University Health Center, Montreal, Canada.
Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
Department of Ophthalmology, St Thomas' Hospital, London, UK.
Institute of Human Genetics, GSF National Research Center for Environment and Health, Munich-Neuherberg, Germany.
Institute of Human Genetics, Technical University Munich, Munich, Germany.
Institut für Zoologie, Johannes Gutenberg University, Mainz, Germany.
Eye Department, Chancellor Wing, St James's University Hospital, Leeds, UK.
Eye and Nutrition Research Group, FLAVIC, National Institute for Research on Agronomy, Dijon, France.
Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
Gene Tech Lab 146/1, Shadman Jail Road, Lahore, Pakistan.
Department of Obstetrics and Gynaecology, King Edward Medical University, Lahore, Pakistan.
Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.
Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA.
Division of Molecular and Cellular Neuroscience, Institute of Ophthalmology, University College London, London, UK.
These authors contributed equally to this work.
Correspondence to: Anneke I den Hollander1,16 e-mail: a.denhollander@antrg.umcn.nl
