Different Functional Outcome of RetGC1 and RPE65 Gene Mutations in Leber Congenital Amaurosis

Perrault, Isabelle; Rozet, Jean–Michel; Ghazi, Imad; Leowski, Corinne; Bonnemaison, Michèle; Gerber, Sylvie; Ducroq, Dominique; Cabot, Annick; Souied, Eric H.; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline

doi:10.1086/302335

Cited by 105 publications

(70 citation statements)

References 13 publications

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“…15 Indeed, photoreceptor cells normally convert light energy into an electrical signal through a transduction process that consists of an enzymatic cascade, resulting in the hydrolysis of cGMP and the closure of cGMP-gated cation channels with hyperpolarisation of the plasma membrane. [16][17][18] The discovery of missense and frameshift retGC-1 mutations suggests that cGMP production in photoreceptor cells is abolished in LCA.…”

Section: Discussionmentioning

confidence: 99%

“…14 The search for genotype-phenotype correlations allowed us to demonstrate that retGC1 gene mutations are responsible for a congenital cone-rod dystrophy with dramatic and invariable cone dysfunction, while RPE65 gene mutations are responsible for a severe yet progressive rod-cone dystrophy, still different from the congenital stationary blindness caused by retGC1 gene mutations. 15 Here we report the study of retGC1 gene in 118 LCA patients. A total of 21 different mutations were identified in 24 unrelated families.…”

Section: Introductionmentioning

confidence: 96%

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Spectrum of retGC1 mutations in Leber's congenital amaurosis

et al. 2000

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Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Genetic heterogeneity of LCA has been suspected since the report by Waardenburg of normal children born to affected parents. In 1995 we localised the first disease causing gene, LCA1, to chromosome 17p13 and confirmed the genetic heterogeneity. In 1996 we ascribed LCA1 to mutations in the photoreceptor-specific guanylate cyclase gene (retGC1). Here, we report on the screening of the whole coding sequence of the retGC1 gene in 118 patients affected with LCA. We found 22 different mutations in 24 unrelated families originating from various countries of the world. It is worth noting that all retGC1 mutations consistently caused congenital cone-rod dystrophy in our series, confirming the previous genotype-phenotype correlations we were able to establish. RetGC1 is an essential protein implicated in the phototransduction cascade, especially in the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. We postulate that the retGC1 mutations hinder the restoration of the basal level of cGMP of cone and rod photoreceptor cells, leading to a situation equivalent to consistent light exposure during photoreceptor development, explaining the severity of the visual disorder at birth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Spectrum of retGC1 mutations in Leber's congenital amaurosis

et al. 2000

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“…Nystagmus and keratoconus have also been documented in patients with Leber congenital amaurosis due to CRX mutations [Sohocki et al, 1998;Jacobson et al, 1998;Dharmaraj et al, 2000;Rivolta et al, 2001]. Patients with Leber congenital amaurosis due to mutations in other genes also can have hyperopia, nystagmus, and keratoconus [Perrault et al, 1999;Lotery et al, 2000;Dharmaraj et al, 2000;Hameed et al, 2000], and thus these ocular abnormalities are not specific to CRX mutations. To determine if patients with CRX mutations causing cone-rod degeneration or retinitis pigmentosa also have a hyperopic refractive error, we tabulated the refractive errors from such cases described in the literature.…”

Section: Clinical Relevancementioning

confidence: 99%

Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX

2001

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We summarize 18 mutations in the human CRX gene that have been associated with Leber congenital amaurosis (congenital retinal blindness), cone-rod degeneration, or retinitis pigmentosa. Except for one obviously null allele not definitely associated with a phenotype (a frameshift in codon 9), all CRX mutations appear to be completely penetrant and cause disease in heterozygotes. These dominant alleles fall into two categories. In one group are missense mutations and short, in-frame deletions; in the second group are frameshift mutations, all of which are in the last exon. All of these dominant mutations are likely to produce stable mRNA that is translated. Mutations in the missense group preferentially affect the conserved homeobox (codons 39-98), and all frameshift mutations leave the homeodomain intact but alter the OTX motif encoded by codons 284-295 at the carboxy terminus. We could not uncover any correlation between type of disease (congenital amaurosis vs. cone-rod degeneration or retinitis pigmentosa) and the type of mutation (missense vs. frameshift). Four of the 18 mutations (approximately 20%) were de novo mutations, and all of these were found in isolate cases of Leber congenital amaurosis. Dominant CRX mutations have not been associated with mental retardation or developmental delay that has sometimes been found in Leber congenital amaurosis caused by other genes. Implications regarding potential future therapies are discussed.

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“…40% of LCA) and a severe yet progressive rod-cone dystrophy (Type II; ca. 60%) [Perrault et al, 1999;Hanein et al, 2004]. 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].…”

Section: Introductionmentioning

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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Different Functional Outcome of RetGC1 and RPE65 Gene Mutations in Leber Congenital Amaurosis

Cited by 105 publications

References 13 publications

Spectrum of retGC1 mutations in Leber's congenital amaurosis

Spectrum of retGC1 mutations in Leber's congenital amaurosis

Dominant Leber congenital amaurosis, cone-rod degeneration, and retinitis pigmentosa caused by mutant versions of the transcription factor CRX

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

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