Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/124982
Title: Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype
Author: Perrault, Isabelle
Estrada-Cuzcano, Alejandro
Lopez, Irma
Kohl, Susanne
Li, Shiqiang
Testa, Francesco
Zekveld, Renate
Pomares, Esther
Aboussair, Nisrine
Banfi, Sandro
Delphin, Nathalie
Den Hollander, Anneke I.
Edelson, Catherine
Florijn, Ralph
Jean-Pierre, Marc
Leowski, Corinne
Megarbane, Andre
Munnich A.
Ren, Huanan
Bergen, Arthur
Chen, Rui
Cremers, Frans P. M.
Gonzàlez-Duarte, Roser
Koenekoop, Robert K.
Simonelli, Francesca
Wissinger, Bernd
Zhang, Qingjiong
Kaplan, Josseline
Rozet, Jean-Michel
Keywords: Retina
Fotoreceptors
Mutació (Biologia)
Retina
Photoreceptors
Mutation (Biology)
Issue Date: 7-Jan-2013
Publisher: Public Library of Science (PLoS)
Abstract: 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*) 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.
Note: Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0051622
It is part of: PLoS One, 2013, vol. 8, num. 1, p. 1-8
URI: http://hdl.handle.net/2445/124982
Related resource: https://doi.org/10.1371/journal.pone.0051622
ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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