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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel lca5 mutations and new genotype-phenotype correlations
Human Mutation, Volume 34, No. 11, Year 2013
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Description
This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials. © 2013 WILEY PERIODICALS, INC.
Authors & Co-Authors
Mackay, Donna S.
United Kingdom, London
Ucl Institute of Ophthalmology
Sweden, Lund
Skånes Universitetssjukhus
Borman, Arundhati Dev
United Kingdom, London
Ucl Institute of Ophthalmology
United Kingdom, London
Moorfields Eye Hospital Nhs Foundation Trust
Sweden, Lund
Skånes Universitetssjukhus
Sui, Ruifang
China, Beijing
Peking Union Medical College Hospital
van den Born, L. Ingeborgh
Netherlands, Rotterdam
Rotterdam Eye Hospital
Berson, Eliot L.
United States, Boston
Massachusetts Eye and Ear
Ocaka, Louise A.
United Kingdom, London
Ucl Institute of Ophthalmology
Davidson, Alice E.
United Kingdom, London
Ucl Institute of Ophthalmology
Heckenlively, John R.
United States, Ann Arbor
University of Michigan Medical School
Branham, Kari
United States, Ann Arbor
University of Michigan Medical School
Ren, Huanan
Canada, Montreal
Centre Universitaire de Santé Mcgill
Lopez, Irma
Canada, Montreal
Centre Universitaire de Santé Mcgill
Maria, Maleeha
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Pakistan, Islamabad
Comsats University Islamabad
Azam, Maleeha S.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Pakistan, Islamabad
Comsats University Islamabad
Henkes, Arjen
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Blokland, Ellen
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Andreasson, Sten
Sweden, Lund
Skånes Universitetssjukhus
de Baere, Elfride B.W.
Belgium, Ghent
Universiteit Gent
Bennett, Jean
United States, Philadelphia
Penn Medicine
Chader, Gerald J.
United States, Los Angeles
Keck School of Medicine of Usc
Berger, Wolfgang
Switzerland, Zurich
Universität Zürich
Golovleva, Irina
Sweden, Umea
Umeå Universitet
Greenberg, Jacquie L.
South Africa, Cape Town
University of Cape Town
Den Hollander, Anneke I.
Netherlands, Nijmegen
Radboud University Medical Center
Klaver, Caroline C.W.
Netherlands, Rotterdam
Erasmus Mc
Klevering, B. Jeroen
Netherlands, Nijmegen
Radboud University Medical Center
Lorenz, Birgit
Germany, Giessen
Justus-liebig-universität Gießen
Preising, Markus
Germany, Giessen
Justus-liebig-universität Gießen
Ramsear, Raj
South Africa, Cape Town
University of Cape Town
Roberts, Lisa J.
South Africa, Cape Town
University of Cape Town
Roepman, Ronald
Netherlands, Nijmegen
Radboud Universiteit
Rohrschneider, K.
Germany, Heidelberg
Universitätsklinikum Heidelberg
Wissinger, Bernd
Germany, Tubingen
Eberhard Karls Universität Tübingen
Qamar, Raheel
Pakistan, Islamabad
Comsats University Islamabad
Pakistan, Hyderabad
Isra University
Webster, Andrew R.
United Kingdom, London
Ucl Institute of Ophthalmology
United Kingdom, London
Moorfields Eye Hospital Nhs Foundation Trust
Cremers, Frans P.M.
Netherlands, Nijmegen
Radboud Institute for Molecular Life Sciences
Belgium, Ghent
Universiteit Gent
Moore, Anthony Tony
United Kingdom, London
Ucl Institute of Ophthalmology
United Kingdom, London
Moorfields Eye Hospital Nhs Foundation Trust
Belgium, Ghent
Universiteit Gent
Koenekoop, Robert K.
Canada, Montreal
Centre Universitaire de Santé Mcgill
Belgium, Ghent
Universiteit Gent
Statistics
Citations: 37
Authors: 37
Affiliations: 23
Identifiers
Doi:
10.1002/humu.22398
ISSN:
10597794
e-ISSN:
10981004
Research Areas
Cancer
Disability
Genetics And Genomics
Health System And Policy
Maternal And Child Health
Study Design
Cross Sectional Study
Cohort Study