西亚试剂：Mutations in LCA5, encoding the ciliary protein lebercilin,

发布时间：2025-05-06

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.

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