title: 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.
authors: Unité de Recherches Génétique et Epigénétique des Maladies Métaboliques, Neurosensorielles et du Développement (INSERM U781)- Université Paris Descartes- Fondation IMAGINE, Paris, France.
authors: Isabelle
authors: I
authors: Perrault
authors: Alejandro
authors: A
authors: Estrada-Cuzcano
authors: Irma
authors: I
authors: Lopez
authors: Susanne
authors: S
authors: Kohl
authors: Shiqiang
authors: S
authors: Li
authors: Francesco
authors: F
authors: Testa
authors: Renate
authors: R
authors: Zekveld-Vroon
authors: Xia
authors: X
authors: Wang
authors: Esther
authors: E
authors: Pomares
authors: Jean
authors: J
authors: Andorf
authors: Nisrine
authors: N
authors: Aboussair
authors: Sandro
authors: S
authors: Banfi
authors: Nathalie
authors: N
authors: Delphin
authors: Anneke I
authors: AI
authors: den Hollander
authors: Catherine
authors: C
authors: Edelson
authors: Ralph
authors: R
authors: Florijn
authors: Marc
authors: M
authors: Jean-Pierre
authors: Corinne
authors: C
authors: Leowski
authors: Andre
authors: A
authors: Megarbane
authors: Cristina
authors: C
authors: Villanueva
authors: Blanca
authors: B
authors: Flores
authors: Arnold
authors: A
authors: Munnich
authors: Huanan
authors: H
authors: Ren
authors: Ditta
authors: D
authors: Zobor
authors: Arthur
authors: A
authors: Bergen
authors: Rui
authors: R
authors: Chen
authors: Frans P M
authors: FP
authors: Cremers
authors: Roser
authors: R
authors: Gonzalez-Duarte
authors: Robert K
authors: RK
authors: Koenekoop
authors: Francesca
authors: F
authors: Simonelli
authors: Edwin
authors: E
authors: Stone
authors: Bernd
authors: B
authors: Wissinger
authors: Qingjiong
authors: Q
authors: Zhang
authors: Josseline
authors: J
authors: Kaplan
authors: Jean-Michel
authors: JM
authors: Rozet
mesh_terms: D000293:Adolescent; D000328:Adult; D002170:Canada; D002648:Child; D002675:Child, Preschool; D002681:China; D015331:Cohort Studies; D005060:Europe; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000473:pathology; D015810:Linkage Disequilibrium; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D014481:United States; D055815:Young Adult
chemical_list: D005136:Eye Proteins; C477438:RD3 protein, human