Isabelle Perrault

Publications (30)103.32 Total impact

• Article: TMEM126A is a mitochondrial located mRNA (MLR) protein of the mitochondrial inner membrane.

  Sylvain Hanein, Mathilde Garcia, Lucas Fares-Taie, Valérie Serre, Yves De Keyzer, Thierry Delaveau, Isabelle Perrault, Nathalie Delphin, Sylvie Gerber, Alain Schmitt, Jean-Marc Masse, Arnold Munnich, Josseline Kaplan, Frédéric Devaux, Jean-Michel Rozet
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  ABSTRACT: BACKGROUND: Hereditary optic neuropathies (HON) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber Hereditary Optic Neuropathy and the autosomal dominant Optic Atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function. METHODS: A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridation, cellular fractionation, mitochondrial membranes association study, mitochondrial sub-compartmentalisation analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out. RESULTS: TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization. CONCLUSION: TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward to a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON. GENERAL SIGNIFICANCE: Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of membrane proteins.
  Biochimica et Biophysica Acta 03/2013; · 4.66 Impact Factor
• Article: [Mutations in NMNAT1 cause Leber congenital amaurosis with severe macular and optic atrophy].

  Josseline Kaplan, Isabelle Perrault, Sylvain Hanein, Hélène Dollfus, Jean-Michel Rozet
  Medecine sciences: M/S 01/2013; 29(1):26-7. · 0.64 Impact Factor
• Article: Union Makes Strength: A Worldwide Collaborative Genetic and Clinical Study to Provide a Comprehensive Survey of RD3 Mutations and Delineate the Associated Phenotype.

  Isabelle Perrault, Alejandro Estrada-Cuzcano, Irma Lopez, Susanne Kohl, Shiqiang Li, Francesco Testa, Renate Zekveld-Vroon, Xia Wang, Esther Pomares, Jean Andorf, [......], Rui Chen, Frans P M Cremers, Roser Gonzalez-Duarte, Robert K Koenekoop, Francesca Simonelli, Edwin Stone, Bernd Wissinger, Qingjiong Zhang, Josseline Kaplan, Jean-Michel Rozet
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  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.
  PLoS ONE 01/2013; 8(1):e51622. · 4.09 Impact Factor
• Article: Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype.

  Isabelle Perrault, Sylvain Hanein, Xavier Gerard, Nathalie Delphin, Lucas Fares-Taie, Sylvie Gerber, Valérie Pelletier, Emilie Mercé, Hélène Dollfus, Bernard Puech, Sabine Defoort-Dhellemmes, Michael D Petersen, Dimitrios Zafeiriou, Arnold Munnich, Josseline Kaplan, Olivier Roche, Jean-Michel Rozet
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  ABSTRACT: Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration. It may present as a congenital stationary cone-rod dystrophy (LCA type I) or a progressive yet severe rod-cone dystrophy (LCA type II). Twelve LCA genes have been identified, three of which account for Type I and nine for LCA type II. All proteins encoded by these genes but two are preferentially expressed in the retina and are responsible for non-syndromic LCA only. By contrast LCA5 and CEP290 are widely expressed and mutations in this latter result in a variety of phenotypes from non-syndromic retinal degeneration to pleiotropic disorders including senior-Loken (SNLS) and Joubert syndromes (JBTS). Recently, mutations in the widely expressed gene SPATA7 were reported to cause LCA or juvenile retinitis pigmentosa. The purpose of this study was i) to determine the level of expression of two major alternative SPATA7 transcripts in a large range of tissues and ii) to assess the involvement of this novel gene in a large cohort of unrelated patients affected with LCA (n = 134). Here, we report high SPATA7expression levels in retina, brain and testis with differential expression of the two transcripts. SPATA7 mutations were identified in few families segregating non-syndromic LCA (n = 4/134). Six different mutations were identified, four of which are novel; All affected both SPATA7 transcripts. The clinical evaluation of patients suggested that SPATA7 mutations account for the rod-cone dystrophy type of the disease.
  Human Mutation 03/2010; 31(3):E1241-50. · 5.69 Impact Factor
• Source

  Available from: Corrado Romano

  Article: Expanding CEP290 mutational spectrum in ciliopathies.

  Lorena Travaglini, Francesco Brancati, Tania Attie-Bitach, Sophie Audollent, Enrico Bertini, Josseline Kaplan, Isabelle Perrault, Miriam Iannicelli, Brunella Mancuso, Luciana Rigoli, [......], A Seward, D G Brooks, A Goldstein, J Caldwell, E Finsecke, B L Maria, K Holden, R P Cruse, K J Swoboda, D Viskochil
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  ABSTRACT: Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
  American Journal of Medical Genetics Part A 09/2009; 149A(10):2173-80. · 2.39 Impact Factor
• Source

  Available from: Dominique Chretien

  Article: TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

  Sylvain Hanein, Isabelle Perrault, Olivier Roche, Sylvie Gerber, Noman Khadom, Marlene Rio, Nathalie Boddaert, Marc Jean-Pierre, Nora Brahimi, Valérie Serre, Dominique Chretien, Nathalie Delphin, Lucas Fares-Taie, Sahran Lachheb, Agnès Rotig, Françoise Meire, Arnold Munnich, Jean-Louis Dufier, Josseline Kaplan, Jean-Michel Rozet
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  ABSTRACT: Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A, in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of unknown function, supporting the view that mitochondrial dysfunction may be a hallmark of inherited optic neuropathies including isolated autosomal-recessive forms.
  The American Journal of Human Genetics 04/2009; 84(4):493-8. · 10.60 Impact Factor
• Article: Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example.

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Nathalie Delphin, David Benezra, Stavit Shalev, Rivka Carmi, Josué Feingold, Jean-Louis Dufier, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet, Marc Jeanpierre
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  ABSTRACT: The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.
  European Journal of HumanGenetics 02/2008; 16(1):115-23. · 4.40 Impact Factor
• Article: Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II.

  Sylvie Gerber, Sylvain Hanein, Isabelle Perrault, Nathalie Delphin, Nisrine Aboussair, Corinne Leowski, Jean-Louis Dufier, Olivier Roche, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet
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  ABSTRACT: 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.
  Human Mutation 01/2008; 28(12):1245. · 5.69 Impact Factor
• Article: Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype.

  Isabelle Perrault, Nathalie Delphin, Sylvain Hanein, Sylvie Gerber, Jean-Louis Dufier, Olivier Roche, Sabine Defoort-Dhellemmes, Hélène Dollfus, Elisa Fazzi, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet
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  ABSTRACT: Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration responsible for congenital blindness. Hitherto, 13 LCA genes have been mapped, nine of which have been identified. Recently, mutations in the NPHP6/CEP290 gene were shown to account for Joubert and Senior-Loken syndromes and to represent a frequent cause of isolated LCA. All LCA patients shared an intronic mutation resulting in an aberrantly spliced transcript and low levels of wild-type transcript that was believed to explain the absence of cerebellar and renal involvement in these patients. Here, we confirm the high frequency of NPHP6/CEP290 mutations in our series of LCA families hailing worldwide (22%). However, we show that conversely to other LCA genes, NPHP6 is involved in families of European descent only (38/38). A total of 24 different mutations were found, 23 of which are novel (one founder mutation in the North region of France). All mutations but two were either nonsense, frameshift, or splice-site changes. The common NPHP6/CEP290 intronic mutation accounted for 43% (33/76) of all disease alleles. Twelve families did not carry this common intronic mutation. At least 10 out of them harboured two mutations expected to truncate the protein questioning the relevance of the assumption according to which the retinal-restricted phenotype in LCA patient could be due to a residual NPHP6/CEP290 activity. Finally, we show that all patients were affected with the cone-rod subtype of the disease whatever their NPHP6/CEP290 genotype.
  Human Mutation 05/2007; 28(4):416. · 5.69 Impact Factor
• Article: Leber congenital amaurosis: survey of the genetic heterogeneity, refinement of the clinical definition and phenotype-genotype correlations as a strategy for molecular diagnosis. Clinical and molecular survey in LCA.

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Gaëlle Tanguy, Jean-Michel Rozet, Josseline Kaplan
  Advances in experimental medicine and biology 02/2006; 572:15-20. · 1.09 Impact Factor
• Source

  Available from: José Alain Sahel

  Article: Disease-associated variants of the rod-derived cone viability factor (RdCVF) in Leber congenital amaurosis. Rod-derived cone viability variants in LCA.

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Hélène Dollfus, Jean-Louis Dufier, Josué Feingold, Arnold Munnich, Shomi Bhattacharya, Josseline Kaplan, José-Alain Sahel, Jean-Michel Rozet, Thierry Leveillard
  Advances in experimental medicine and biology 02/2006; 572:9-14. · 1.09 Impact Factor
• Article: A first locus for isolated autosomal recessive optic atrophy (ROA1) maps to chromosome 8q21-q22.

  Fabienne Barbet, Sylvie Gerber, Sélim Hakiki, Isabelle Perrault, Sylvain Hanein, Dominique Ducroq, Gaëlle Tanguy, Jean-Louis Dufier, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet
  Advances in experimental medicine and biology 02/2006; 572:21-7. · 1.09 Impact Factor
• Chapter: Leber Congenital Amaurosis: Survey of the Genetic Heterogeneity, Refinement of the Clinical Definition and Phenotype-Genotype Correlations as a Strategy for Molecular Diagnosis

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Gaëlle Tanguy, Jean-Michel Rozet, Josseline Kaplan
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  ABSTRACT: Leber congenital amaurosis (LCA, MIM 204000) is the earliest and most severe form of all hereditary retinal dystrophies, responsible for congenital blindness. Its frequency, estimated until recently to 5% of all inherited retinal dystrophies1, has been re-evaluated as some LCA cases might represent the extreme end of a spectrum of severity of retinal dystrophies.2–4
  12/2005: pages 15-20;
• Source

  Available from: José Alain Sahel

  Chapter: Disease-Associated Variants of the Rod-derived Cone Viability Factor (RdCVF) in Leber Congenital Amaurosis

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Hélène Dollfus, Jean-Louis Dufier, Josué Feingold, Arnold Munnich, Shomi Bhattacharya, Josseline Kaplan, José-Alain Sahel, Jean-Michel Rozet, Thierry Leveillard
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  ABSTRACT: Leber congenital amaurosis (LCA) is the most early and severe form of all inherited retinal dystrophies, responsible for congenital blindness. The genetic heterogeneity of LCA has been accepted for a long time but it turned out to be largely higher than all odds. So far, 11genes have been mapped on human chromosomes and eight identified. i) the retinal specific guanylate cyclase gene (GUCY2D, retGC1; 17p13.1; LCA1; MIM 600179), ii) the gene encoding the 65-kD protein specific to the retinal pigment epithelium (RPE65; 1p31; LCA2; MIM180069), iii) the cone-rod homeobox-containing gene (CRX; 19q13.3; LCA7; MIM 60225), iv) the gene encoding the arylhydrocarbon receptor interacting protein-like 1 (AIPL1; 17p13.1; LCA; MIM 604392), v) the gene encoding the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1; 14q11; LCA6; MIM 605446), vi) the human homologue of the drosophila melanogater crumbs gene (CRB1; 1q31; LCA8; MIM 604210), vii) the gene encoding the tubby-like protein 1 (TULP1; 6q21.3; LCA10; MIM 602280), viii) the retinol dehydrogenase 12 (RDH12; 14q24; LCA11; MIM 608830), ix) LCA3 (14q24; MIM 604232), x) LCA5 (6q11-16; MIM 604537) and xi) LCA9 (1p36; MIM608553).
  12/2005: pages 9-14;
• Article: Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles.

  Jana Zernant, Maigi Külm, Sharola Dharmaraj, Anneke I den Hollander, Isabelle Perrault, Markus N Preising, Birgit Lorenz, Josseline Kaplan, Frans P M Cremers, Irene Maumenee, Robert K Koenekoop, Rando Allikmets
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  ABSTRACT: Leber congenital amaurosis (LCA) is an early-onset inherited disorder of childhood blindness characterized by visual impairment noted soon after birth. Variants in at least six genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) have been associated with a diagnosis consistent with LCA or early-onset retinitis pigmentosa (RP). Genetically heterogeneous inheritance complicates the analyses of LCA cases, especially in patients without a family history of the disorder, and conventional methods are of limited value. To overcome these limitations, arrayed primer extension (APEX) technology was used to design a genotyping microarray for early-onset, severe retinal degenerations that includes all of the >300 disease-associated variants currently described in eight genes (in addition to the six just listed, the early-onset RP genes LRAT and MERTK were added). The resultant LCA array allows simultaneous detection of all known disease-associated alleles in any patient with early-onset RP. The array was validated by screening 93 confirmed patients with LCA who had known mutations. Subsequently, 205 novel LCA cases were screened on the array, followed by segregation analyses in families, if applicable. The microarray was >99% effective in determining the existing genetic variation and yielded at least one disease-associated allele in approximately one third of the novel patients. More than two (expected) variants were discovered in a substantial fraction (22/300) of the patients, suggesting a modifier effect from more than one gene. In support of the latter hypothesis, the third allele segregated with a more severe disease phenotype in at least five families. The LCA genotyping microarray is a robust and cost-effective screening tool, representing the prototype of a disease chip for genotyping patients with a genetically heterogeneous condition. Simultaneous screening for all known LCA-associated variants in large LCA cohorts allows systematic detection and analysis of genetic variation, facilitating prospective diagnosis and ultimately predicting disease progression.
  Investigative Ophthalmology &amp Visual Science 10/2005; 46(9):3052-9. · 3.60 Impact Factor
• Article: A novel mutation in the GUCY2D gene responsible for an early onset severe RP different from the usual GUCY2D-LCA phenotype.

  Isabelle Perrault, Sylvain Hanein, Sylvie Gerber, Beatrice Lebail, Patrice Vlajnik, Fabienne Barbet, Dominique Ducroq, Jean-Louis Dufier, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet
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  ABSTRACT: Patients carrying mutations in the retinal guanylate cyclase (GUCY2D) gene were reported to be constantly affected with a particular form of Leber congenital amaurosis (LCA) defined as a "congenital stationary cone-rod dystrophy with high hypermetropia, panretinal degeneration and highly reduced visual acuity". We report here, the study of two patients affected with different retinal disorder: a typical GUCY2D-LCA phenotype and early-onset severe retinitis pigmentosa (RP). Unexpectedly, they gave birth to an infant suffering from LCA. The genetic study in the family allowed to explain the disease in the infant by showing that the GUCY2D-LCA disease was accounted for by compound heterozygosity for two severe GUCY2D mutations (c.3043+4A>T, c.2943delG) while the early-onset severe RP resulted from homozygosity for a 4 bp insertion in the same gene, despite the sound phenotypic differences (c.3236insACCA). Interestingly, this last mutation is excepted to result in a 28 amino acid elongation of the protein contrary to all GUCY2D mutations accounting for LCA which are expected to be null alleles. This report gives support to the existence of exceptional GUCY2D mutations accounting for a milder and different phenotype compared to the typical GUCY2D congenital stationary cone-rod dystrophy.
  Human Mutation 02/2005; 25(2):222. · 5.69 Impact Factor
• Article: [Leber congenital amaurosis: retinol dehydrogenases are the culprit].

  Isabelle Perrault, Sylvain Hanein, Josseline Kaplan
  Medecine sciences: M/S 01/2005; 20(12):1066-8. · 0.64 Impact Factor
• Source

  Available from: ncbi.nlm.nih.gov

  Article: Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis.

  Isabelle Perrault, Sylvain Hanein, Sylvie Gerber, Fabienne Barbet, Dominique Ducroq, Helene Dollfus, Christian Hamel, Jean-Louis Dufier, Arnold Munnich, Josseline Kaplan, Jean-Michel Rozet
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  ABSTRACT: Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia.
  The American Journal of Human Genetics 11/2004; 75(4):639-46. · 10.60 Impact Factor
• Article: The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations.

  Sharola Dharmaraj, Bart P Leroy, Melanie M Sohocki, Robert K Koenekoop, Isabelle Perrault, Khalid Anwar, Shagufta Khaliq, R Summathi Devi, David G Birch, Elaine De Pool, Natalio Izquierdo, Lionel Van Maldergem, Mohammad Ismail, Annette M Payne, Graham E Holder, Shomi S Bhattacharya, Alan C Bird, Josseline Kaplan, Irene H Maumenee
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  ABSTRACT: To describe the phenotype of Leber congenital amaurosis (LCA) in 26 probands with mutations in aryl hydrocarbon receptor interacting protein-like 1 protein (AIPL1) and compare it with phenotypes of other LCA-related genes. To describe the electroretinogram (ERG) in heterozygote carriers. Patients with AIPL1-related LCA were identified in a cohort of 303 patients with LCA by polymerase chain reaction single-strand confirmational polymorphism mutation screening and/or direct sequencing. Phenotypic characterization included clinical and ERG evaluation. Seven heterozygous carrier parents also underwent ERG testing. Seventeen homozygotes and 9 compound heterozygotes were identified. The W278X mutation was most frequent (48% of alleles). Visual acuities ranged from light perception to 20/400. Variable retinal appearances, ranging from near normal to varying degrees of chorioretinal atrophy and intraretinal pigment migration, were noted. Atrophic and/or pigmentary macular changes were present in 16 (80%) of 20 probands. Keratoconus and cataracts were identified in 5 (26%) of 19 patients, all of whom were homozygotes. The ERG of a parent heterozygote carrier revealed significantly reduced rod function, while ERGs for 6 other carrier parents were normal. The phenotype of LCA in patients with AIPL1 mutations is relatively severe, with a maculopathy in most patients and keratoconus and cataract in a large subset. Rod ERG abnormalities may be present in heterozygous carriers of AIPL1 mutations. Understanding and recognizing the phenotype of LCA may help in defining the course and severity of the disease. Identifying the gene defect is the first step in preparation for therapy since molecular diagnosis in LCA will mandate the choice of treatment.
  Archives of Ophthalmology 08/2004; 122(7):1029-37. · 3.71 Impact Factor
• Article: Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis.

  Sylvain Hanein, Isabelle Perrault, Sylvie Gerber, Gaëlle Tanguy, Fabienne Barbet, Dominique Ducroq, Patrick Calvas, Hélène Dollfus, Christian Hamel, Tuija Lopponen, Francis Munier, Louisa Santos, Stavit Shalev, Dimitrios Zafeiriou, Jean-Louis Dufier, Arnold Munnich, Jean-Michel Rozet, Josseline Kaplan
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  ABSTRACT: Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype-phenotype correlations were found that allowed us to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rod-cone dystrophy. Besides, objective ophthalmologic data allowed us to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth.
  Human Mutation 05/2004; 23(4):306-17. · 5.69 Impact Factor