Retinal Dehydrogenase 12 (RDH12) Mutations in Leber Congenital Amaurosis

Perrault, Isabelle; Hanein, Sylvain; Gerber, Sylvie; Barbet, Fabienne; Ducroq, Dominique; Dollfus, Hélène; Hamel, Christian; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline; Rozet, Jean–Michel

doi:10.1086/424889

Cited by 155 publications

(123 citation statements)

References 25 publications

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“…5B). These findings fit well with the established roles for RA in the development of the retina (14,16,25) and in RPE abnormalities found in Apc and Rxr␣ knockout mice (19,20). Loss of RA production in the developing retina offers an explanation for the presence of retinal defects, such as congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium, commonly present in familial adenomatous polyposis patients.…”

Section: Resultssupporting

confidence: 86%

“…For example, Hyatt et al (17) demonstrated that zebrafish treated with exogenous RA displayed an enhancement of ventral retina characteristics, whereas knockdown of an enzyme involved in RA biosynthesis (bcox) hindered the establishment of the ventral retina (18). In addition, recent studies show that targeted deletion of the retinoid receptor RXR␣ within the mouse retinal pigmented epithelium (RPE) caused RPE abnormalities, including the appearance of congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium-like lesions similar to those present in mice bearing mutated APC (19,20).…”

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confidence: 99%

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Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Nadauld

Chidester

Shelton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium is an ocular lesion found in patients harboring mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. We report that Apc-deficient zebrafish display developmental abnormalities of both the lens and retina. Injection of dominantnegative Lef reduced Wnt signaling in the lens but did not rescue retinal differentiation defects. In contrast, treatment of apc mutants with all-trans retinoic acid rescued retinal differentiation defects but had no apparent effect on the lens. We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC. Morpholino knockdown of Rdh5 phenocopied the apc mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid. Microarray analyses of apc mutants and Rdh5 morphants revealed a profound overlap in the transcriptional profile of these embryos. These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for APC mutation-associated retinal defects such as congenital hypertrophy͞hyperplasia of the retinal pigmented epithelium.colon cancer ͉ retina ͉ APC

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Section: Resultssupporting

confidence: 86%

mentioning

confidence: 99%

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Nadauld

Chidester

Shelton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…This observation raises the question to know whether non-truncating mutations of this gene could be involved in autosomal recessive retinal dystrophies less severe than LCA. Indeed, LCA-associated mutations are commonly deleterious mutations and mutations in several LCA genes can be responsible for autosomal recessive retinal dystrophies (retinitis pigmentosa or cone-rod dystrophies) [Gu et al, 1997;Freund et al, 1997;Banerjee et al, 1998;Sohocki et al, 1998;Lewis et al, 1999;den Hollander 1999;Lorenz et al, 2000;den Hollander et al, 2001;Sohocki et al, 2001;Thompson et al, 2001Thompson et al, , 2002Hameed et al, 2003;den Hollander et al, 2004;Janecke et al, 2004;Perrault et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

“…Up to date, 13 LCA genes have been mapped, 10 of which have been identified: GUCY2D/retGC1 [Perrault et al, 1996], RPE65 [Marlhens et al, 1997], CRX [Swaroop et al, 1999], AIPL1 [Sohocki et al, 2000], RPGRIP1 [Dryja et al, 2001;Gerber et al, 2001], CRB1 [den Hollander et al, 2001;Gerber et al, 2002], LRAT [Thompson and Gal, 2003], TULP1 , RDH12 [Janecke et al, 2004;Perrault et al, 2004], CEP290 [den Hollander et al, 2006;Perrault et al, 2007]. Mutations in 3/10of them were shown to account for LCA type I (GUCY2D, RPGRIP1, CEP290) while, although less frequent, LCA type II was hitherto accounted for by mutations in 7/10 genes (RPE65, CRX, AIPL1, CRB1, LRAT TULP12, RDH12) [Perrault et al, 1999;Hanein et al, 2004;Perrault et al, 2004;Perrault et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

et al. 2007

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Leber congenital amaurosis (LCA) is the earliest and most severe form of inherited retinal dystrophy responsible for blindness or severe visual impairment at birth or within the first months of life. Up to date, ten LCA genes have been identified. Three of them account for ca. 43% of families and are responsible for a congenital severe stationary cone-rod dystrophy (Type I, 60 % of LCA) while the seven remaining genes account for 32% of patients and are responsible for a progressive yet severe rod-cone dystrophy (Type II, 40 % of LCA ). Recently, mutations in LCA5, encoding the ciliary protein lebercilin, were reported to be a rare cause of leber congenital amaurosis. The purpose of this study was to evaluate the involvement of this novel gene and to look for genotype-phenotype correlations. Here we report the identification of three novel LCA5 mutations (3/3 homozygous) in three families confirming the modest implication of this gene in our series (3/179; 1.7%). Besides, we suggest that the phenotype of these patients affected with a particularly severe form of LCA type II may represent a continuum with LCA type I.

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“…It can also present with bull's eye-type macular changes and macular coloboma-like lesions. 1 Genetic defects in GUCY2D (retinal guanylate cyclase, 17p13.1), 2 AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1, 17p13.2), 3 CRB1 (Crumbs homolog 1, 1q31.3), 4 CRX (photoreceptor specific cone-rod homeobox transcription factor, 19q13.32), 5 RPE65 (retinal pigment epithelium specific 65 kDa protein, 1p31.2), 6 RPGRIP1 (retinitis pigmentosa GTPase regulator-interacting protein 1, 14q11.2), 7 RDH12 (retinal dehydrogenase 12, 14q24.1) 8 and TULP1 (Tubby-like protein 1, 6p21.31) 9 have been associated with LCA. Additionally, three independent loci with unidentified genes, LCA3 (14q24), 10 LCA5 (6q11-q16), 11 and LCA9 (1p36) 12 have been found to show linkage to LCA.…”

Section: Introductionmentioning

confidence: 99%

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

Özgül

Bozkurt²,

Kıratlı

et al. 2005

Eye

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Background Leber's congenital amaurosis (LCA) is an inherited retinal dystrophy, which causes severe visual impairment in early childhood. Recent molecular genetic studies have linked 11 loci (AIPL1, CRB1, CRX, GUCY2D, RPE65, RDH12, RPGRIP1, TULP1, LCA3, LCA5, and LCA9) to LCA. LCA5 is a new locus, which maps to the 6q11-q16 chromosomal region and was found to be associated with macular coloboma-type LCA in a Pakistani family. Herein, we describe the molecular genetic features of a consanguineous Turkish family in which four children have macular colobomatype LCA. Methods Haplotype analysis was performed on the DNA of the family members using microsatellite markers against GUCY2D, RPE65, and LCA5. Genomic DNA was screened for mutations by means of singlestrand conformational polymorphism (SSCP) analysis in exons of the RPE65 and CRX genes. Results In haplotype analysis, no linkage to LCA5 or GUCY2D loci was detected. None of the tested markers showed homozygosity or segregation between affected siblings. PCR-SSCP mutation analysis revealed no mutations in the screened RPE65 and CRX genes. Conclusion We excluded LCA5 as the genetic cause of macular coloboma-type LCA in this Turkish family. Macular coloboma-type LCA shows genetic heterogeneity and it is not possible to establish a phenotype-genotype correlation with LCA5 and macular coloboma.

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Retinal Dehydrogenase 12 (RDH12) Mutations in Leber Congenital Amaurosis

Cited by 155 publications

References 25 publications

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Dual roles for adenomatous polyposis coli in regulating retinoic acid biosynthesis and Wnt during ocular development

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

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