Dataset Information

Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

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.

SUBMITTER: Perrault I

PROVIDER: S-EPMC3538699 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

Perrault Isabelle I Estrada-Cuzcano Alejandro A Lopez Irma I Kohl Susanne S Li Shiqiang S Testa Francesco F Zekveld-Vroon Renate R Wang Xia X Pomares Esther E Andorf Jean J Aboussair Nisrine N Banfi Sandro S Delphin Nathalie N den Hollander Anneke I AI Edelson Catherine C Florijn Ralph R Jean-Pierre Marc M Leowski Corinne C Megarbane Andre A Villanueva Cristina C Flores Blanca B Munnich Arnold A Ren Huanan H Zobor Ditta D Bergen Arthur A Chen Rui R Cremers Frans P M FP Gonzalez-Duarte Roser R Koenekoop Robert K RK Simonelli Francesca F Stone Edwin E Wissinger Bernd B Zhang Qingjiong Q Kaplan Josseline J Rozet Jean-Michel JM

PloS one 20130107 1

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 homoz ...[more]

PMID: 23308101

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Dataset Information

Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

Publications

Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype.

Similar Datasets

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