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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype
PLoS ONE, Volume 8, No. 1, Article e51622, Year 2013
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Description
Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration (RD), and the most common cause of incurable blindness diagnosed in children. It is occasionally the presenting symptom of multisystemic ciliopathies which diagnosis will require a specific care of patients. Nineteen LCA genes are currently identified and three of them account for both non-syndromic and syndromic forms of the disease. RD3 (LCA12) was implicated as a LCA gene based on the identification of homozygous truncating mutations in two LCA families despite the screening of large cohorts of patients. Here we provide a comprehensive survey of RD3 mutations and of their clinical expression through the screening of a cohort of 852 patients originating worldwide affected with LCA or early-onset and severe RD. We identified three RD3 mutations in seven unrelated consanguineous LCA families - i.e., a 2 bp deletion and two nonsense mutations - predicted to cause complete loss of function. Five families originating from the Southern Shores of the Mediterranean segregated a similar mutation (c.112C>T, p.R38&z.ast;) suggesting that this change may have resulted from an ancient founder effect. Considering the low frequency of RD3 carriers, the recurrence risk for LCA in non-consanguineous unions is negligible for both heterozygote and homozygote RD3 individuals. The LCA12 phenotype in our patients is highly similar to those of patients with mutant photoreceptor-specific guanylate cyclase (GUCY2D/LCA1). This observation is consistent with the report of the role of RD3 in trafficking of GUCYs and gives further support to a common mechanism of photoreceptor degeneration in LCA12 and LCA1, i.e., inability to increase cytoplasmic cGMP concentration in outer segments and thus to recover the dark-state. Similar to LCA1, LCA12 patients have no extraocular symptoms despite complete inactivation of both RD3 alleles, supporting the view that extraocular investigations in LCA infants with RD3 mutations should be avoided. © 2013 Perrault et al.
Authors & Co-Authors
Perrault, Isabelle
France, Paris
Inserm
Estrada-Cuzcano, Alejandro
Netherlands, Nijmegen
Radboud University Medical Center
Lopez, Irma
Canada, Montreal
Centre Universitaire de Santé Mcgill, Hôpital de Montreal Pour Enfants
Kohl, Susanne
Germany, Tubingen
Universitätsklinikum Und Medizinische Fakultät Tübingen
Li, Shiqiang
China, Guangzhou
Zhongshan Ophthalmic Center
Testa, Francesco
Italy, Naples
Università Degli Studi Della Campania Luigi Vanvitelli
Zekveld-Vroon, Renate
Netherlands, Amsterdam
Nederlands Herseninstituut
Wang, Xia
United States, Houston
Baylor College of Medicine
Pomares, Esther
Spain, Barcelona
Universitat de Barcelona
Andorf, Jeaneen L.
United States, Iowa City
University of Iowa Carver College of Medicine
Aboussair, Nisrine
Morocco, Marakech
Université Cadi Ayyad
Banfi, Sandro
Italy, Naples
Tigem Telethon Institute of Genetics and Medicine
Italy, Naples
Università Degli Studi Della Campania Luigi Vanvitelli
Delphin, Nathalie
France, Paris
Inserm
Den Hollander, Anneke I.
Netherlands, Nijmegen
Radboud University Medical Center
Edelson, Catherine
France, Paris
Fondation Adolphe de Rothschild
Florijn, Ralph
Netherlands, Amsterdam
Nederlands Herseninstituut
Jean-Pierre, Marc
France, Paris
Institut Cochin
Leowski, Corinne
France, Paris
Institut National Des Jeunes Aveugles
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Villanueva, Cristina
Mexico, Mexico City
Asociación Para Evitar la Ceguera en México, I.a.p.
Flores, Blanca
Mexico, Mexico City
Asociación Para Evitar la Ceguera en México, I.a.p.
Münnich, Arnold
France, Paris
Inserm
Ren, Huanan
Canada, Montreal
Centre Universitaire de Santé Mcgill, Hôpital de Montreal Pour Enfants
Zobor, Ditta
Germany, Tubingen
Universitätsklinikum Und Medizinische Fakultät Tübingen
Bergen, Arthur
Netherlands, Amsterdam
Nederlands Herseninstituut
Chen, Rui
United States, Houston
Baylor College of Medicine
Cremers, Frans P.M.
Netherlands, Nijmegen
Radboud University Medical Center
Gonzalez-Duarte, Roser
Spain, Barcelona
Universitat de Barcelona
Koenekoop, Robert K.
Canada, Montreal
Centre Universitaire de Santé Mcgill, Hôpital de Montreal Pour Enfants
Simonelli, Francesca
Italy, Naples
Università Degli Studi Della Campania Luigi Vanvitelli
Stone, Edwin M.
United States, Iowa City
University of Iowa Carver College of Medicine
Wissinger, Bernd
Germany, Tubingen
Universitätsklinikum Und Medizinische Fakultät Tübingen
Zhang, Qingjiong
China, Guangzhou
Zhongshan Ophthalmic Center
Kaplan, Josseline C.
France, Paris
Inserm
Rozet, Jean Michel
France, Paris
Inserm
Statistics
Citations: 35
Authors: 35
Affiliations: 17
Identifiers
Doi:
10.1371/journal.pone.0051622
e-ISSN:
19326203
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Maternal And Child Health
Study Design
Cross Sectional Study
Cohort Study
Study Approach
Quantitative