J M Rozet

Université René Descartes - Paris 5, Lutetia Parisorum, Île-de-France, France

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Publications (71)376.24 Total impact

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    ABSTRACT: Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.
    No preview · Article · Oct 2016 · Advances in Experimental Medicine and Biology
  • P. Calvas · N. Chassaing · J. Kaplan · J.M. Rozet

    No preview · Article · Oct 2015
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    Full-text · Article · Jul 2015 · Cilia
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    Preview · Article · Jul 2015 · Cilia
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    Full-text · Dataset · Dec 2014
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    ABSTRACT: Background Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. Methods We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families. Results We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity. Conclusions Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.
    Full-text · Article · Oct 2014 · Journal of Medical Genetics

  • No preview · Article · Feb 2013
  • I Perrault · JM Rozet · A Munnich · J Kaplan

    No preview · Article · Jul 2012
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    ABSTRACT: Leber congenital amaurosis (LCA) is the earliest and most severe inherited retinal degeneration. Isolated forms of LCA frequently result from mutation of the CEP290 gene which is expressed in various ciliated tissues. Seven LCA patients with CEP290 mutations were investigated to study otorhinolaryngologic phenotype and respiratory cilia. Nasal biopsies and brushing were performed to study cilia ultrastructure using transmission electron microscopy and ciliary beating using high-speed videomicroscopy, respectively. CEP290 expression in normal nasal epithelium was studied using real-time RT-PCR. When electron microscopy was feasible (5/7), high levels of respiratory cilia defects were detected. The main defects concerned dynein arms, central complex and/or peripheral microtubules. All patients had a rarefaction of ciliated cells and a variable proportion of short cilia. Frequent but moderate and heterogeneous clinical and ciliary beating abnormalities were found. CEP290 was highly expressed in the neural retina and nasal epithelial cells compared with other tissues. These data provide the first clear demonstration of respiratory cilia ultrastructural defects in LCA patients with CEP290 mutations. The frequency of these findings in LCA patients along with the high expression of CEP290 in nasal epithelium suggest that CEP290 has an important role in the proper development of both the respiratory ciliary structures and the connecting cilia of photoreceptors. The presence of respiratory symptoms in patients could represent additional clinical criteria to direct CEP290 genotyping of patients affected with the genetically heterogeneous cone-rod dystrophy subtype of LCA.
    Full-text · Article · Dec 2010 · Journal of Medical Genetics
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    ABSTRACT: Leber congenital amaurosis (LCA) is a the earliest and most severe form of retinal dystrophy responsible for congenital blindness. LCA has genetic heterogeneity and the study of this disease is elucidating the genetics and molecular interactions involved in the development of the retina. To date, 11 LCA genes have been mapped, ten of which have been identified. The CEP290 gene has been shown to account for Joubert and Senior-Loken syndromes and to be a frequent cause of nonsyndromic LCA. We report here the first Arab patient, born to consanguineous parents, with Leber congenital amaurosis attributable to mutation of the CEP290 gene.
    No preview · Article · Feb 2010 · Journal francais d'ophtalmologie
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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. © 2009 Wiley-Liss, Inc.
    No preview · Article · Oct 2009 · American Journal of Medical Genetics Part A

  • No preview · Article · Apr 2009 · Journal Français d Ophtalmologie
  • Josseline Kaplan · Jean‐Michel Rozet

    No preview · Chapter · Dec 2008
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    ABSTRACT: L’amaurose congénitale de Leber (ACL) est la plus précoce et la plus sévère de toutes les dystrophies rétiniennes héréditaires. À ce jour, 7 gènes différents ont été reconnus comme responsables de la maladie. Ces gènes sont tous exprimés préférentiellement dans les photorécepteurs ou l’épithélium pigmentaire de la rétine, mais ils sont impliqués dans des mécanismes physiopathologiques extraordinairement différents entraînant une variabilité physiopathogénique inattendue. Cette hétérogénéité génétique et physiologique qui pourrait s’accroître grandement dans les prochaines années gêne considérablement l’analyse moléculaire des patients. Toutefois, ce génotypage est indispensable pour définir des sous-groupes de patients prêts pour les thérapeutiques du futur. Nous avons effectué une analyse des 7 gènes identifiés dans une large série de 179 familles indépendantes comprenant 52 cas familiaux et 127 cas sporadiques (27/127 nés d’un mariage consanguin). Des mutations ont été identifiées chez 47,5 % des patients. GUCY2D est de loin le gène le plus fréquemment impliqué dans notre série (21,2 %), suivi par CRB1 (10 %), RPE65 (6,1 %), RPGRIP1 (4,5 %), AIPL1 (3,4 %), TULP1 (1,7 %) et CRX (0,6 %). L’histoire clinique de tous les patients portant des mutations a été soigneusement reconsidérée à la recherche de différences cliniques. De solides corrélations phénotype-génotype ont été mises en évidence qui permettent de différencier les patients en 2 groupes principaux. Le premier comprend tous les patients dont les symptômes concordent avec la définition traditionnelle de l’ACL, c’est-à-dire, une dégénérescence rétinienne congénitale ou très précoce, stationnaire, de type « cone-rod dystrophy » tandis que le second groupe rassemble des patients atteints d’une dégénérescence rétinienne certes précoce et sévère mais évolutive de type « rod-cone dystrophy ». De plus, l’analyse des données ophtalmologiques a permis de subdiviser chacun des groupes en 2 sous-groupes corrélés à des gènes sélectionnés. Sur la base de ces données, un arbre décisionnel a été dessiné permettant d’orienter l’analyse moléculaire des gènes d’ACL chez un nouveau patient. Cet arbre décisionnel qui devrait alléger la lourde tâche de génotypage, souligne l’absolue nécessité d’obtenir une histoire clinique la plus précise possible depuis la naissance.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 pathophysiologic variety. This broad genetic and physiologic heterogeneity, which could greatly increase in the coming years, hinders molecular diagnosis in LCA patients. Genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here we report a comprehensive mutational analysis of all the known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% of patients. GUCY2D accounted for by far the largest part of the LCA cases in 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 in the search for phenotype variations. Genotype-phenotype correlations were found that made it possible 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. In addition, objective ophthalmologic data subdivided 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 onerous task of genotyping new patients, but only if the most precise clinical history since birth is available.
    No preview · Article · Jan 2005 · Journal Français d Ophtalmologie
  • J.-M. Rozet · S. Gerber · D. Ducroq · C. Hamel · J.-L. Dufier · J. Kaplan
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    ABSTRACT: Hereditary macular dystrophies are degenerative diseases of the central area of the retina associating primary anomalies of the retinal pigment epithelium and sensory retina. These conditions, whose hallmark is a loss of visual acuity, are a major cause of blindness and affect patients at all ages. Macular dystrophies group diseases that are heterogenous at the genetic level, as well as at the clinical, histological and physiopathological levels. Monogenic macular dystrophies are rare autosomal dominant conditions, with the exception of Stargardt disease in its typical form, which is not only relatively frequent but is also inherited as an autosomal recessive trait. During the last few years, the molecular bases of these conditions have begun to be elucidated with the identification of several responsible genes. For some macular dystrophies, this new information has confirmed pre-existing hypotheses on their pathophysiology, but for others, the discovery of the disease gene has added further complexity to the disease process. Two contradictory concepts were particularly highlighted by these genetic studies. Several phenotypes previously described as different clinical entities were brought together by the identification of mutations in the same gene, and converselyome conditions that were clinically assigned the same name, often heterogeneous at the clinical level, appeared genetically and physiopathologically heterogeneous. In addition, it is worth noting that the monogenic macular dystrophy genes were often regarded as potential factors for susceptibility to age-related macular degenerations. However, to date, only ABCA4 mutations have been associated with a minority of this frequent multifactorial condition. The aim of this article is to give a progress report on the monogenic macular dystrophy genes and to review current knowledge concerning the pathophysiology of these conditions.
    No preview · Article · Jan 2005 · Journal Français d Ophtalmologie
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    ABSTRACT: Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. Eight LCA loci have been mapped, but only six out of eight genes have been hitherto identified. A genome-wide screen for homozygosity was conducted in a large consanguineous family originating from Palestine, for which no mutation was found in any of the six known LCA genes and that excluded the LCA3 and LCA5 loci. Evidence for homozygosity, however, was found in all affected patients of the family on chromosome 1q31, a region in which the human homologue of the Drosophila melanogaster crumbs gene (CRB1) has been mapped. Consequently, we proposed a hypothesis that the disease-causing mutation in this family might lie in an unexplored region of this LCA gene. As a matter of fact, while no mutation was found in any of the 11 CRB1 exons originally reported, we identified a 10-bp (del 4121-4130) deletion segregating with the disease in a later reported 12th exon lying in the 3' end of the gene. Interestingly, this deletion disrupts an amino acid sequence that was shown to be crucial for the function of the protein in the Drosophila counterpart (CRB).
    No preview · Article · Jan 2003 · Ophthalmic Genetics
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    ABSTRACT: Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. So far, six LCA loci have been mapped but only 4 out of 6 genes have been identified. A genome-wide screen for homozygosity was conducted in seven consanguineous families unlinked to any of the six LCA loci. Evidence for homozygosity was found in two of these seven families at the 14q11 chromosomal region. Two retinal specific candidate genes were known to map to this region, namely the neural retina leucine zipper (NRL) and the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1). No mutation of the NRL gene was found in any of the two families. Thus, we determined the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 encompasses 24 coding exons, nine of which are first described here with their corresponding exon-intron boundaries. The screening of the gene in the two families consistent with linkage to chromosome 14q11 allowed the identification of a homozygous null mutation and a homozygous missense mutation, respectively. Further screening of LCA patients unlinked to any of the four already identified LCA genes (n=86) identified seven additional mutations in six of them. In total, eight distinct mutations (5 out of 8 truncating) in 8/93 patients were found. So far this gene accounts for eight out of 142 LCA cases in our series (5.6%).
    Full-text · Article · Sep 2001 · European Journal of HumanGenetics
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    ABSTRACT: Leber congenital amaurosis (LCA) is the earliest and the most severe form of all inherited retinal dystrophies. In 1996, the current investigators ascribed the disease in families linked to the LCA1 locus on chromosome 17p13.1 to mutations in the photoreceptor-specific guanylyl cyclase (retGC-1) gene. So far, 22 different mutations, of which 11 are missense mutations, have been identified in 25 unrelated families. This is a report of the functional analyses of nine of the missense mutations. cDNA constructs were generated that contained the retGC-1 missense mutations identified in patients related to the LCA1 locus. Mutants were expressed in COS7 cells and assayed for their ability to hydrolyze guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). All mutations lying in the catalytic domain showed a complete abolition of cyclase activity. In contrast, only one mutation lying in the extracellular domain also resulted in a severely reduced catalytic activity, whereas the others showed completely normal activity. More than half the mutations identified in patients related to the LCA1 locus are truncating mutations expected to result in a total abolition of retGC-1 activity. Concerning missense mutations, half of them lying in the catalytic domain of the protein also result in the complete inability of the mutant cyclases to hydrolyze GTP into cGMP in vitro. In contrast, missense mutations lying in the extracellular domain, except one affecting the initiation codon, showed normal catalytic activity of retGC-1. Nevertheless, considering that all patients related to the LCA1 locus displayed the same phenotype, it can be assumed that all missense mutations would have the same dramatic consequences on protein activity in vivo as truncation mutations.
    Full-text · Article · Jun 2001 · Investigative Ophthalmology & Visual Science
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    ABSTRACT: The last Crypto-Jews (Marranos) are the survivors of Spanish Jews who were persecuted in the late fifteenth century, escaped to Portugal and were forced to convert to save their lives. Isolated groups still exist in mountainous areas such as Belmonte in the Beira-Baixa province of Portugal. We report here the genetic study of a highly consanguineous endogamic population of Crypto-Jews of Belmonte affected with autosomal recessive retinitis pigmentosa (RP). A genome-wide search for homozygosity allowed us to localize the disease gene to chromosome 15q22-q24 (Zmax=2.95 at theta=0 at the D15S131 locus). Interestingly, the photoreceptor cell-specific nuclear receptor (PNR) gene, the expression of which is restricted to the outer nuclear layer of retinal photoreceptor cells, was found to map to the YAC contig encompassing the disease locus. A search for mutations allowed us to ascribe the RP of Crypto-Jews of Belmonte to a homozygous missense mutation in the PNR gene. Preliminary haplotype studies support the view that this mutation is relatively ancient but probably occurred after the population settled in Belmonte.
    No preview · Article · Oct 2000 · Human Genetics
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    ABSTRACT: 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.
    Full-text · Article · Sep 2000 · European Journal of HumanGenetics

Publication Stats

3k Citations
376.24 Total Impact Points


  • 2010-2014
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 1999
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1998
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1996
    • McGill University
      Montréal, Quebec, Canada
  • 1993
    • SickKids
      Toronto, Ontario, Canada