Garder des muscles forts : de l’identification des gènes au développement de traitements pour les maladies neuromusculaires héréditaires

Tous nos muscles sont capables de produire une force qui se traduit en mouvement. Il existe trois types de tissus musculaires : les muscles cardiaques, qui sont uniques au cœur, les muscles lisses, qui constituent le support de tous nos organes et vaisseaux sanguins, et les muscles squelettiques qui pour la plupart sont attachés aux os et sont responsables de la locomotion. Parmi ces trois types de muscles, seuls les muscles squelettiques sont soumises à notre contrôle volontaire.

Les maladies neuromusculaires héréditaires (NMDs pour ‘NeuroMuscular Disorders’) forment un groupe hétérogène de maladies qui affecte la fonction des muscles squelettiques. Elles sont caractérisées par un affaiblissement progressif des muscles ainsi qu’une perte de masse musculaire et peuvent entraîner des handicaps chroniques, représentant ainsi une lourde charge à porter pour les patients et leurs familles, ainsi que pour nos systèmes de santé publique. Ces maladies peuvent être divisées en deux groupes : les myopathies qui sont associées à des défauts dans la structure elle-même des muscles, et les neuropathies qui elles sont des maladies du système nerveux dues à des défauts dans les nerfs qui contrôlent les mouvements musculaires. Comme pour l’étude de toute autre maladie génétique, une étape cruciale dans l’étude des NMDs consiste en l’identification des gènes qui en sont responsables. Ceci est important non seulement pour pouvoir mieux diagnostiquer ces troubles, mais aussi pour comprendre les mécanismes moléculaires pathologiques qui entraînent le développement des maladies, et pouvoir développer de nouvelles stratégies thérapeutiques. Le département NeMus combine des approches multi-omiques, des données cliniques, des échantillons biologiques, des modèles prédictifs et des outils bioinformatiques pour étudier les NMDs. Cette approche polyvalente a permis à ses scientifiques d’apporter d’importantes avancées au domaine des NMDs dont notamment une nouvelle approche thérapeutique prometteuse.

La dernière décennie a vu le développement du séquençage de nouvelle génération (NGS) qui a révolutionné les domaines de la recherche et du diagnostic. Il est désormais possible de séquencer rapidement les génomes des patients, ce qui permet de collecter et de comparer un nombre incroyable de données génomiques, extrêmement utiles pour identifier les causes génétiques de diverses maladies. Cette technologie a été fondamentale au département NeMus dans l’identification de nombreux gènes et mutations impliqués dans les maladies neuromusculaires.



L’analyse de l’incroyable masse de données issues du NGS et leur comparaison à des profils cliniques complexes nécessitent cependant le développement de systèmes et d’outils bioinformatique solides. L’équipe « Bioinformatique et Génétique » dirigée par le Pr. Christophe Béroud a développé plusieurs systèmes de référence pour répondre à toutes les étapes de la recherche translationnelle et qui sont aujourd’hui les systèmes les plus performants dans la prédiction de pathogénicité (UMD-Predictor et HSF couplés au système d’annotation et de filtration VarAFT). Leur objectif est d’identifier rapidement les mutations responsables des maladies en question parmi la masse de variation génétique ‘innocente’ que l’on trouve normalement dans les génomes de différents individus.  Grâce à cette expertise, l’équipe dirige les études cliniques bioinformatiques du Projet Européen RD-Connect FP7 et travaille à présent sur la construction de deux bases de données relatives aux maladies rares, la première répertoriant les variations de nombre de copies dans ces maladies (BAnque Nationale des CNV COnstitutionnels – BANCCO), et la deuxième répertoriant tous les variants génétiques identifiés par NGS (French Rare Disease Variant Database - RDVD). Les chercheurs ont par ailleurs établit des bases de données dénombrant les mutations trouvées dans divers gènes impliqués dans le cancer, notamment pour les gènes BRCA1 et BRCA2 impliqués dans le cancer du sein et des ovaires, ou encore dans des gènes responsables de NMDs. Ils ont également établit des registres de patients  qui rassemblent les renseignements génétiques et cliniques connus pour une maladie donnée. Les chercheurs ont par exemple développé les registres globaux du réseau TREAT-NMD, ainsi que l’Observatoire National Français des patients atteints de dystrophie musculaire Facio-Scapulo-Humérale (DMFSH), une maladie qui touche essentiellement les muscles du visage, des épaules et des avant-bras. Ce dernier contient les données de plus de 450 patients et est aujourd’hui le plus important registre de patients DMFSH au monde.

L’étude des données cliniques et génétiques de la DMFSH est essentielle pour comprendre les mécanismes moléculaires qui mènent au développement de la pathologie, une quête qui occupe le laboratoire du Dr. Frédérique Magdinier depuis plusieurs années.

La plupart des patients atteints de DMFSH (95%) sont porteurs d’une mutation génétique sur le chromosome 4, en position 4q35. Elle est située à proximité d’une des extrémités du chromosome, appelées télomères, dans la région dite subtélomérique. Cette région contient une ‘répétition D4Z4’, une séquence d’ADN dans laquelle une unité de base D4Z4 est répétée plusieurs fois en tandem. Les individus non atteints portent normalement entre 11 et 150 unités D4Z4 à ce site, alors que les patients DMFSH portent une mutation qui consiste en une contraction de la répétition avec seulement 1 à 10 de ces unités. Cependant, contrairement à d’autres maladies génétiques, cette mutation se situe en dehors de tout gène et n’altère donc pas la fonction d’une protéine. Par contre, elle interfère localement avec la chromatine, la structure qui emballe et compacte l’ADN à l’intérieur du noyau de la cellule. L’ADN peut être plus ou moins compacté, ce qui le rend plus au moins accessible et permissif à l’expression des gènes qu’il comporte. Chez les individus sains, les répétitions D4Z4 sont associées à une chromatine hautement compactée et une expression quasi-nulle des gènes avoisinants. Ces deux caractéristiques sont cependant perdues chez les patients DMFSH porteurs de la contraction D4Z4.

Les chercheurs du laboratoire de Dr. Frédérique Magdinier ont apporté d’importants éléments de réponse à ces observations. Ils ont en effet démontré il y a quelques années que la version courte de la répétition D4Z4 est capable d’interagir avec CTCF, une protéine capable de modifier la structure de la chromatine. De plus, l’équipe a révélé que cette même version courte de la répétition D4Z4 est relocalisée à la périphérie du noyau, sous-domaine nucléaire impliqué dans la régulation de la chromatine.

D’un point de vue clinique, les premiers signes de DMFSH n’apparaissent normalement qu’à partir de l’adolescence, ce qui signifie que les patients présentent des muscles d’apparence normale pendant au moins une dizaine d’années. Pour comprendre pourquoi ces muscles fonctionnels tout à coup deviennent défaillants, le Dr. Frédérique Magdinier et son équipe ont décidé de s’intéresser aux caractéristiques moléculaires des muscles présymptomatiques au cours du développement.

«  Nous avons observé que chez le fœtus les muscles présentent déjà des défauts similaires à ceux de patients DMFSH adultes », explique le Dr. Frédérique Magdinier. « De plus, l’expression des gènes impliqués dans le développement musculaire est globalement dérégulée. Nos résultats ont ainsi révélé que malgré l’apparence normale des muscles avant l’apparition des premiers symptômes chez les patients, des défauts existent déjà au cours du développement embryonnaire ».

Par l’étude de larges cohortes de patients présentant les signes typiques de la DMFSH, ainsi que d’individus sains porteurs de la mutation, l’équipe a par ailleurs découvert que la méthylation de l’ADN, un des changements épigénétiques caractéristiques de la maladie, présente des niveaux extrêmement variables entre individus.  Les chercheurs ont également identifié des réarrangements chromosomiques complexes chez certains patients, soulignant ainsi la complexité du locus D4Z4 lié à la maladie.

L’ensemble de ces résultats démontre qu’il est crucial d’étudier en détail les changements épigénétiques et la structure de la chromatine au cours du développement musculaire pour comprendre les mécanismes pathologiques qui mènent à la DMFSH. Les projets de l’équipe visent à étudier la différentiation des cellules musculaires, ainsi que les mécanismes moléculaires qui expliquent le lien entre l’organisation structurale du locus 4q35 et la pathologie.  Pour cela, les chercheurs développent actuellement de nouveaux modèles cellulaires de la maladie dont des modèles basés sur des cellules iPS (cellules pluripotentes induites).

Les dysferlinopathies sont un groupe de maladies neuromusculaires très hétérogènes qui présentent des symptomes plus ou moins sévères. Elles sont toutes liées à des mutations du gène de la Dysferline (DYSF) qui code pour une large protéine nécessaire lors de la survenue d’une lésion pour réparer la membrane enveloppant les fibres musculaires. À ce jour,  plus de 400 mutations différentes dans le gène ont été associées à des maladies de cette famille. Les chercheurs du MMG ont beaucoup d’expérience dans le diagnostic des dysferlinopathies et ont largement contribué à identifier ces mutations. Dans le cadre de ses activités de diagnostic, le laboratoire du Dr. Marc Bartoli a récemment créé une base de données publique qui rassemble toutes les mutations identifiées chez des patients et leurs familles, ainsi que les données cliniques disponibles pour chaque individu. Cette base de données est un outil essentiel pour cliniciens et chercheurs afin de mieux comprendre ces maladies.

Au delà de l’intérêt que l’équipe porte au diagnostic, le Dr. Marc Bartoli et ses collègues cherchent à développer des stratégies thérapeutiques pour le traitement des dysferlinopathies. Ils travaillent actuellement sur le développement d’une méthode basé sur le saut d’exon, une technique qui exploite la structure même des gènes et les mécanismes qu‘ils subissent lors de leur expression.

Le saut d’exon – en quoi consiste-t-il?

Les gènes sont composés de deux types d ‘éléments intercalés: les exons et les introns. Les exons contiennent les séquences qui seront traduites en protéine, alors que les introns sont des séquences non-codantes qui devront être éliminés avant cette traduction. La première étape de l’expression d’un gène est sa transcription, un processus par lequel l’ensemble des exons et des introns du gène est recopié sous forme d’un acide nucléique appelé ARN. Les introns sont ensuite excisés et les exons accolés les uns aux autres par un mécanisme appelé épissage. L’ARN mature qui en résulte est finalement traduit en protéine.

Le saut d’exon est une technique utilisée en thérapie génique qui exploite le mécanisme d’épissage de l’ARN. Son but est d’induire l’épissage de l’exon porteur de la mutation délétère de telle façon à ce qu’il ne soit plus traduit. La protéine ainsi produite est incomplète et peut ne pas être entièrement fonctionnelle, mais dans certains cas elle l’est suffisamment pour corriger les défauts causés par la protéine mutée. Cette méthode s’est avérée prometteuse pour le traitement de la myopathie de Duchenne, une maladie génétique provoquant une dégénérescence progressive de l’ensemble des muscles.

Le saut exon peut-il être utilisé pour traiter les dysferlinopathies ?

La première tentative de saut d’exon entreprise par l’équipe du Dr. Marc Bartoli se base sur un patient porteur d’une version du gène DYSF dépourvue de son exon 32 mais atteint d’une dysferlinopathie légère. Les chercheurs ont donc pensé qu’une protéine dépourvue de l’information contenue dans cet exon devait être suffisamment fonctionnelle pour corriger des cas de dysferlinopathies plus sévères.

« Nous avons étudié l’effet du saut de l’exon 32 sur des cellules dérivées de deux patients. De manière surprenante, alors que la nouvelle protéine ne s’exprime que faiblement, les cellules sont devenues compétentes pour réparer des lésions au niveau de leurs membranes, indiquant que la thérapie fonctionne correctement»,  déclare le Dr. Marc Bartoli.

Ces résultats démontrent le potentiel de la technique de saut d’exon pour le traitement des dysferlinopathies. Alors que des études pré-cliniques chez la souris sont en cours pour le saut de l’exon 32 de la dysferline, l’équipe développe des approches similaires pour le traitement d’autres maladies neuromusculaires.

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Portilho, DM.  et al. 2015

miRNA Expression in Control and FSHD Fetal Human Muscle Biopsies

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Salort-Campana, E.  et al. 2015

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

BACKGROUND: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35....
Orphanet J Rare Dis - issue: - volume: 10 - pages: 2.

Salort-Campana, E.  et al. 2015

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

BACKGROUND: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35....
Orphanet J Rare Dis - issue: - volume: 10 - pages: 2.

Bartoli, M.  et al. 2014

Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients

INTRODUCTION: Autosomal recessive muscular dystrophies are heterogeneous genetic disorders, with 39 genes currently implicated. Genetic diagnosis using targeted single-gene analysis by Sanger...
Muscle Nerve - issue: 6 - volume: 50 - pages: 1007-1010.

Badja, C.  et al. 2014

Efficient and Cost-Effective Generation of Mature Neurons From Human Induced Pluripotent Stem Cells

For years, our ability to study pathological changes in neurological diseases has been hampered by the lack of relevant models until the recent groundbreaking work from Yamanaka's group showing that...
Stem Cells Transl. Med. - issue: 12 - volume: 3 - pages: 1467-1472.

Kergourlay, V.  et al. 2014

Identification of splicing defects caused by mutations in the dysferlin gene

Missense, iso-semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to...
Hum. Mutat. - issue: 12 - volume: 35 - pages: 1532-1541.

Badja, C.  et al. 2014

Efficient and cost-effective generation of mature neurons from human induced pluripotent stem cells

For years, our ability to study pathological changes in neurological diseases has been hampered by the lack of relevant models until the recent groundbreaking work from Yamanaka's group showing that...
Stem Cells Transl Med - issue: 12 - volume: 3 - pages: 1467-1472.

Robin, JD.  et al. 2014

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor...
Genes Dev. - issue: 22 - volume: 28 - pages: 2464-2476.

Robin, JD.  et al. 2014

Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor...
Genes Dev. - issue: 22 - volume: 28 - pages: 2464-2476.

Puppo, F.  et al. 2014

Molecular defects in FAT1 are associated to facioscapulohumeral dystrophy (FSHD)

WOS:000342870200023
Neuromusc. Disord. - issue: 9-10 - volume: 24 - pages: 797-798.

Jaka, O.  et al. 2014

Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a...
Muscle Nerve - issue: 3 - volume: 50 - pages: 448-453.

Gaillard, M.  et al. 2014

Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers

OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and...
Neurology - issue: 8 - volume: 83 - pages: 733-742.

Gaillard, M.  et al. 2014

Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers

OBJECTIVE: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and...
Neurology - issue: 8 - volume: 83 - pages: 733-742.

Mazuc, E.  et al. 2014

In-Cell Intrabody Selection from a Diverse Human Library Identifies C12orf4 Protein as a New Player in Rodent Mast Cell Degranulation

The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate...
PLoS One - issue: 8 - volume: 9 - pages: e104998.

Thompson, R.  et al. 2014

RD-Connect: An Integrated Platform Connecting Databases, Registries, Biobanks and Clinical Bioinformatics for Rare Disease Research

Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype,...
J. Gen. Intern. Med. - issue: - volume: 29 - pages: S780-S787.

Etienne-Grimaldi, M.  et al. 2014

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study

Background: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative...
Br. J. Cancer - issue: 11 - volume: 110 - pages: 2728-2737.

Boennemann, CG.  et al. 2014

Diagnostic approach to the congenital muscular dystrophies

Congenital muscular dystrophies (CMDs) are early onset disorders of muscle with histological features suggesting a dystrophic process. The congenital muscular dystrophies as a group encompass great...
Neuromusc. Disord. - issue: 4 - volume: 24 - pages: 289-311.

Vassallo, PF.  et al. 2014

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic...
Blood - issue: 13 - volume: 123 - pages: 2116-2126.

Vassallo, PF.  et al. 2014

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic...
Blood - issue: 13 - volume: 123 - pages: 2116-2126.

Robellet, X.  et al. 2014

A Genetic Screen for Functional Partners of Condensin in Fission Yeast

Mitotic chromosome condensation is a prerequisite for the accurate segregation of chromosomes during cell division, and the conserved condensin complex a central player of this process. However, how...
G3-Genes Genomes Genet. - issue: 2 - volume: 4 - pages: 373-381.

Bladen, CL.  et al. 2014

Mapping the differences in care for 5,000 Spinal Muscular Atrophy patients, a survey of 24 national registries in North America, Australasia and Europe

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the...
J. Neurol. - issue: 1 - volume: 261 - pages: 152-163.

Ferreboeuf, M.  et al. 2014

DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first...
Hum. Mol. Genet. - issue: 1 - volume: 23 - pages: 171-181.

Callier, P.  et al. 2013

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males...
Clin. Genet. - issue: 6 - volume: 84 - pages: 507-521.

Poulain, S.  et al. 2013

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in...
Am. J. Hematol. - issue: 11 - volume: 88 - pages: 948-954.

Bladen, CL.  et al. 2013

The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no...
Hum. Mutat. - issue: 11 - volume: 34 - pages: 1449-1457.

Broucqsault, N.  et al. 2013

Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy

Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is...
Hum. Mol. Genet. - issue: 20 - volume: 22 - pages: 4206-4214.

Broucqsault, N.  et al. 2013

Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy

Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is...
Hum. Mol. Genet. - issue: 20 - volume: 22 - pages: 4206-4214.

Robin, JD.  et al. 2013

Length dependent telomere looping affects long-distant gene expression (5 Mb) in FSHD

WOS:000324972500271
Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 824-824.

Ferreboeuf, M.  et al. 2013

DUX 4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

WOS:000324972500267
Neuromusc. Disord. - issue: 9-10 - volume: 23 - pages: 823-823.

Roudaut, C.  et al. 2013

Restriction of calpain3 expression to the skeletal muscle prevents cardiac toxicity and corrects pathology in a murine model of limb-girdle muscular dystrophy

BACKGROUND: Genetic defects in calpain3 (CAPN3) lead to limb-girdle muscular dystrophy type 2A, a disease of the skeletal muscle that affects predominantly the proximal limb muscles. We previously...
Circulation - issue: 10 - volume: 128 - pages: 1094-1104.

Humbertclaude, V.  et al. 2013

Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD...
Rev. Neurol. - issue: 8-9 - volume: 169 - pages: 583-594.

Boussouar, A.  et al. 2013

Acacetin and chrysin, two polyphenolic compounds, alleviate telomeric position effect in human cells

We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We...
Mol Ther Nucleic Acids - issue: - volume: 2 - pages: e116.

Boussouar, A.  et al. 2013

Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells

We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We...
Mol. Ther.-Nucl. Acids - issue: - volume: 2 - pages: e116.

McDonnell, CM.  et al. 2013

Ecto- and endoparasite induce similar chemical and brain neurogenomic responses in the honey bee (Apis mellifera)

Background: Exclusion from a social group is an effective way to avoid parasite transmission. This type of social removal has also been proposed as a form of collective defense, or social immunity, in...
BMC Ecol. - issue: - volume: 13 - pages: 25.

Caruso, N.  et al. 2013

Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy

Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts....
PLoS Genet. - issue: 6 - volume: 9 - pages: e1003550.

Caruso, N.  et al. 2013

Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy

Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts....
PLoS Genet. - issue: 6 - volume: 9 - pages: e1003550.

Diala, I.  et al. 2013

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/beta-catenin signalling pathway in...
EMBO Rep. - issue: 4 - volume: 14 - pages: 356-363.

Diala, I.  et al. 2013

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

The DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/β-catenin signalling pathway in human...
EMBO Rep. - issue: 4 - volume: 14 - pages: 356-363.

Blandin, G.  et al. 2013

A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome

BACKGROUND: The complexity of the skeletal muscle and the identification of numerous human disease-causing mutations in its constitutive proteins make it an interesting tissue for proteomic studies...
Skelet Muscle - issue: 1 - volume: 3 - pages: 3.

Boehm, J.  et al. 2013

Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced...
Am. J. Hum. Genet. - issue: 2 - volume: 92 - pages: 271-278.

Roche, S.  et al. 2013

Comparative analysis of protein expression of three stem cell populations: Models of cytokine delivery system in vivo

Several mechanisms mediate the regenerative and reparative capacity of stem cells, including cytokine secretion; therefore these cells can act as delivery systems of therapeutic molecules. Here we...
Int. J. Pharm. - issue: 1 - volume: 440 - pages: 72-82.

Lostal, W.  et al. 2012

Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy

Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea...
PLoS ONE - issue: 5 - volume: 7 - pages: e38036.

Galati, A.  et al. 2012

TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner

Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin...
PLoS ONE - issue: 4 - volume: 7 - pages: e34386.

De Paula, AM.  et al. 2012

Further heterogeneity in myopathy with tubular aggregates?


Muscle Nerve - issue: 6 - volume: 46 - pages: 984-985.

Eyrnard, B.  et al. 2012

Diagnostic strategy for limb-girdle muscular dystrophies

Limb-girdle muscular dystrophies represent a major chapter of genetic myopathies. Many different entities have been identified, most of them with recessive transmission, a minority with dominant...
Rev. Neurol. - issue: 12 - volume: 168 - pages: 919-926.

Herbaux, C.  et al. 2012

B-Cell-Specific Transcription Factor BACH2 Involved in the Clinical Behavior Heterogeneity of Waldenstrom Macroglobulinemia

WOS:000313838902278
Blood - issue: 21 - volume: 120 - pages: .

Carmignac, V.  et al. 2012

In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome...
Am. J. Hum. Genet. - issue: 5 - volume: 91 - pages: 950-957.

Fahiminiya, S.  et al. 2012

Improvement of 2D-PAGE Resolution of Human, Porcine and Canine Follicular Fluid: Comparison of Two Immunodepletion Columns

Contents Follicular fluid provides the microenvironment within which somatic cells proliferate and differentiate, and the oocyte matures. It contains a number of soluble factors implicated in various...
Reprod. Domest. Anim. - issue: 5 - volume: 47 - pages: e67-e70.

Salgado, D.  et al. 2012

MyMiner: a web application for computer-assisted biocuration and text annotation

Motivation: The exponential growth of scientific literature has resulted in a massive amount of unstructured natural language data that cannot be directly handled by means of bioinformatics tools....
Bioinformatics - issue: 17 - volume: 28 - pages: 2285-2287.

Boehm, J.  et al. 2012

Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei....
Hum. Mutat. - issue: 6 - volume: 33 - pages: 949-959.

Galati, A.  et al. 2012

TRF2 Controls Telomeric Nucleosome Organization in a Cell Cycle Phase-Dependent Manner

Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin...
PLoS One - issue: 4 - volume: 7 - pages: e34386.

Blandin, G.  et al. 2012

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare...
Hum. Mutat. - issue: 3 - volume: 33 - pages: E2317-2331.

Humbertclaude, V.  et al. 2012

Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials

Aims: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). Methods: The French dystrophinopathy database provided clinical, histochemical and molecular data of...
Eur. J. Paediatr. Neurol. - issue: 2 - volume: 16 - pages: 149-160.

Bonnans, C.  et al. 2012

Essential requirement for beta-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

beta-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/beta-catenin, the major actor in human colorectal cancer initiation. To better understand the roles of...
Proc. Natl. Acad. Sci. U. S. A. - issue: 8 - volume: 109 - pages: 3047-3052.

Soheili, T.  et al. 2012

Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications

Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (α-, β-, γ-, and δ-sarcoglycan) form a...
Hum. Mutat. - issue: 2 - volume: 33 - pages: 429-439.

Samadi, A.  et al. 2012

Surgical management of patients with Marfan syndrome: Evolution throughout the years

Aim. To evaluate the evolution of surgical management in a large population of patients with Marfan syndrome. Methods. This is a retrospective study of patients fulfilling the Ghent criteria for...
Arch. Cardiovasc. Dis. - issue: 2 - volume: 105 - pages: 84-90.

Jondeau, G.  et al. 2012

Aortic Event Rate in the Marfan Population A Cohort Study

Background-Optimal management, including timing of surgery, remains debated in Marfan syndrome because of a lack of data on aortic risk associated with this disease. Methods and Results-We used our...
Circulation - issue: 2 - volume: 125 - pages: 226-232.

Bartoli, M.  et al. 2012

Validation of comparative genomic hybridization arrays for the detection of genomic rearrangements of the calpain-3 and dysferlin genes


Clin. Genet. - issue: 1 - volume: 81 - pages: 99-101.

Krahn, M.  et al. 2011

Eosinophilic infiltration related to CAPN3 mutations: a pathophysiological component of primary calpainopathy?


Clin. Genet. - issue: 4 - volume: 80 - pages: 398-402.

Barthélémy, F.  et al. 2011

Translational research and therapeutic perspectives in dysferlinopathies

Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with...
Mol. Med. - issue: 9-10 - volume: 17 - pages: 875-882.

Simonet, T.  et al. 2011

The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms involved in chromosome-end protection. However, very little is known on the binding...
Cell Res. - issue: 7 - volume: 21 - pages: 1028-1038.

Laure, L.  et al. 2010

A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-kappa B pathway in skeletal muscle

A multiprotein complex encompassing a transcription regulator, cardiac ankyrin repeat protein ( CARP), and the calpain 3 protease was identified in the N2A elastic region of the giant sarcomeric...
FEBS J. - issue: 20 - volume: 277 - pages: 4322-4337.

Krahn, M.  et al. 2010

A naturally occurring human minidysferlin protein repairs sarcolemmal lesions in a mouse model of dysferlinopathy

Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair....
Sci Transl Med - issue: 50 - volume: 2 - pages: 50ra69.

Lévy, N.  et al. 2010

Therapeutic exon 'switching' for dysferlinopathies?


Eur. J. Hum. Genet. - issue: 9 - volume: 18 - pages: 969-970; author reply 971.

Ye, J.  et al. 2010

TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage

Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding...
Cell - issue: 2 - volume: 142 - pages: 230-242.

Falandry, C.  et al. 2010

CLLD8/KMT1F is a lysine methyltransferase that is important for chromosome segregation

Proteins bearing a SET domain have been shown to methylate lysine residues in histones and contribute to chromatin architecture. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an...
J. Biol. Chem. - issue: 26 - volume: 285 - pages: 20234-20241.

Ourliac-Garnier, I.  et al. 2010

Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1

Telomeres, the nucleoprotein complexes located at the ends of chromosomes, are involved in chromosome protection and genome stability. Telomeric repeat binding factor 1 (TRF1) and telomeric repeat...
J. Biol. Inorg. Chem. - issue: 5 - volume: 15 - pages: 641-654.

Lostal, W.  et al. 2010

Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer

Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair,...
Hum. Mol. Genet. - issue: 10 - volume: 19 - pages: 1897-1907.

Arnoult, N.  et al. 2010

Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization

The mechanisms governing telomere replication in humans are still poorly understood. To fill this gap, we investigated the timing of replication of single telomeres in human cells. Using in situ...
PLoS Genet. - issue: 4 - volume: 6 - pages: e1000920.

Wein, N.  et al. 2010

Efficient bypass of mutations in dysferlin deficient patient cells by antisense-induced exon skipping

Mutations in DYSF encoding dysferlin cause primary dysferlinopathies, autosomal recessive diseases that mainly present clinically as Limb Girdle Muscular Dystrophy type 2B and Miyoshi myopathy. More...
Hum. Mutat. - issue: 2 - volume: 31 - pages: 136-142.

Krahn, M.  et al. 2010

Exclusion of mutations in the dysferlin alternative exons 1 of DYSF-v1, 5a, and 40a in a cohort of 26 patients

Mutations in the gene encoding dysferlin (DYSF; MIM# 603009, 2p13, GenBank NM_003494.2) cause primary dysferlinopathies, which are autosomal recessive muscular dystrophies. DYSF has a large mutational...
Genet Test Mol Biomarkers - issue: 1 - volume: 14 - pages: 153-154.

Ottaviani, A.  et al. 2010

D4Z4 as a prototype of CTCF and lamins-dependent insulator in human cells

Using cellular models that mimic the organizations of the subtelomeric 4q35 locus found in patients affected with Facio-Scapulo-Humeral Dystrophy (FSHD) and in healthy individuals, we recently...
Nucleus - issue: 1 - volume: 1 - pages: 30-36.

Mellgren, RL.  et al. 2009

Calcium-dependent plasma membrane repair requires m- or mu-calpain, but not calpain-3, the proteasome, or caspases

Mechanically damaged plasma membrane undergoes rapid calcium-dependent resealing that appears to depend, at least in part, on calpain-mediated cortical cytoskeletal remodeling. Cells null for Capns1,...
Biochim. Biophys. Acta - issue: 12 - volume: 1793 - pages: 1886-1893.

Ottaviani, A.  et al. 2009

Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF

The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning...
EMBO J. - issue: 16 - volume: 28 - pages: 2428-2436.

Horard, B.  et al. 2009

Global analysis of DNA methylation and transcription of human repetitive sequences

Half of the human genome consists of repetitive DNA sequences. Recent studies in various organisms highlight the role of chromatin regulation of repetitive DNA in gene regulation as well as in...
Epigenetics - issue: 5 - volume: 4 - pages: 339-350.

Laure, L.  et al. 2009

Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling

In an attempt to identify potential therapeutic targets for the correction of muscle wasting, the gene expression of several pivotal proteins involved in protein metabolism was investigated in...
FEBS J. - issue: 3 - volume: 276 - pages: 669-684.

Ottaviani, A.  et al. 2009

The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy

Both genetic and epigenetic alterations contribute to Facio-Scapulo-Humeral Dystrophy (FSHD), which is linked to the shortening of the array of D4Z4 repeats at the 4q35 locus. The consequence of this...
PLoS Genet. - issue: 2 - volume: 5 - pages: e1000394.

Bartoli, M.  et al. 2008

Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation

Limb girdle muscular dystrophy type 2D (LGMD2D, OMIM600119) is a genetic progressive myopathy that is caused by mutations in the human alpha-sarcoglycan gene (SGCA). Here, we have introduced in mice...
Hum. Mol. Genet. - issue: 9 - volume: 17 - pages: 1214-1221.

Benayoun, B.  et al. 2008

NF-kappa B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in the cysteine protease calpain 3 (CAPN3) that leads to selective muscle wasting. We previously...
Faseb J. - issue: 5 - volume: 22 - pages: 1521-1529.

Ottaviani, A.  et al. 2008

Telomeric position effect: from the yeast paradigm to human pathologies?

Alteration of the epigenome is associated with a wide range of human diseases. Therefore, deciphering the pathways that regulate the epigenetic modulation of gene expression is a major milestone for...
Biochimie - issue: 1 - volume: 90 - pages: 93-107.

Daniele, N.  et al. 2007

Ins and outs of therapy in limb girdle muscular dystrophies

Muscular dystrophies are hereditary degenerative muscle diseases that cause life-long disability in patients. They comprise the well-known Duchenne Muscular Dystrophy (DMD) but also the group of Limb...
Int. J. Biochem. Cell Biol. - issue: 9 - volume: 39 - pages: 1608-1624.

Bartoli, M.  et al. 2007

AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiency

Myostatin is a negative regulator of muscle mass whose inhibition has been proposed as a therapeutic strategy for muscle-wasting conditions. Indeed, blocking myostatin action through different...
Gene Ther. - issue: 9 - volume: 14 - pages: 733-740.

Milic, A.  et al. 2007

A third of LGMD2A biopsies have normal calpain 3 proteolytic activity as determined by an in vitro assay

Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive muscular disorder caused by mutations in the gene coding for calpain 3, a calcium-dependent protease. We developed an in vitro...
Neuromuscul. Disord. - issue: 2 - volume: 17 - pages: 148-156.

Fougerousse, F.  et al. 2007

Phenotypic correction of alpha-sarcoglycan deficiency by intra-arterial injection of a muscle-specific serotype 1 rAAV vector

alpha-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in alpha-sarcoglycan, a transmembrane protein part of the...
Mol. Ther. - issue: 1 - volume: 15 - pages: 53-61.

Bartoli, M.  et al. 2006

A mouse model for monitoring calpain activity under physiological and pathological conditions

Calpains are Ca(2+)-dependent cysteine proteases known to be important for the regulation of cell functions and which aberrant activation causes cell death in a number of degenerative disorders. To...
J. Biol. Chem. - issue: 51 - volume: 281 - pages: 39672-39680.

Duguez, S.  et al. 2006

Calpain 3: a key regulator of the sarcomere?

Calpain 3 is a 94-kDa calcium-dependent cysteine protease mainly expressed in skeletal muscle. In this tissue, it localizes at several regions of the sarcomere through binding to the giant protein,...
FEBS J. - issue: 15 - volume: 273 - pages: 3427-3436.

Bartoli, M.  et al. 2006

Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A

Calpainopathy (limb-girdle muscular dystrophy type 2A, LGMD2A) is a recessive muscular disorder caused by deficiency in the calcium-dependent cysteine protease calpain 3. To date, no treatment exists...
Mol. Ther. - issue: 2 - volume: 13 - pages: 250-259.

Bartoli, M.  et al. 2006

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies

Muscular dystrophies are a genetically and phenotypically heterogeneous group of degenerative muscle diseases. A subset of them are due to genetic deficiencies in proteins which form the...
Gene Ther. - issue: 1 - volume: 13 - pages: 20-28.

Auriol, E.  et al. 2005

Specific binding of the methyl binding domain protein 2 at the BRCA1-NBR2 locus

The methyl-CpG binding domain (MBD) proteins are key molecules in the interpretation of DNA methylation signals leading to gene silencing. We investigated their binding specificity at the...
Nucleic Acids Res. - issue: 13 - volume: 33 - pages: 4243-4254.

Defossez, P.  et al. 2005

The human enhancer blocker CTC-binding factor interacts with the transcription factor Kaiso

CTC-binding factor (CTCF) is a DNA-binding protein of vertebrates that plays essential roles in regulating genome activity through its capacity to act as an enhancer blocker. We performed a yeast...
J. Biol. Chem. - issue: 52 - volume: 280 - pages: 43017-43023.

Bartoli, M.  et al. 2005

Calpains in muscle wasting

Calpains are intracellular nonlysosomal Ca(2+)-regulated cysteine proteases. They mediate regulatory cleavages of specific substrates in a large number of processes during the differentiation, life...
Int. J. Biochem. Cell Biol. - issue: 10 - volume: 37 - pages: 2115-2133.

Stockholm, D.  et al. 2005

Imaging calpain protease activity by multiphoton FRET in living mice

Constant efforts are ongoing for the development of new imaging methods that allow the investigation of molecular processes in vivo. Protein-protein interactions, enzymatic activities and...
J. Mol. Biol. - issue: 1 - volume: 346 - pages: 215-222.

Felsenfeld, G.  et al. 2004

Chromatin boundaries and chromatin domains


Cold Spring Harb. Symp. Quant. Biol. - issue: - volume: 69 - pages: 245-250.

Magdinier, F.  et al. 2004

Both CTCF-dependent and -independent insulators are found between the mouse T cell receptor alpha and Dad1 genes

The T cell rearrangement of the T cell receptor (TCR) genes TCRalpha and delta is specifically regulated by a complex interplay between enhancer elements and chromatin structure. The alpha enhancer is...
J. Biol. Chem. - issue: 24 - volume: 279 - pages: 25381-25389.

Fourel, G.  et al. 2004

Insulator dynamics and the setting of chromatin domains

The early discovery of cis-regulatory elements able to promote transcription of genes over large distances led to the postulate that elements, termed insulators, should also exist that would limit the...
Bioessays - issue: 5 - volume: 26 - pages: 523-532.

Taveau, M.  et al. 2003

Calpain 3 is activated through autolysis within the active site and lyses sarcomeric and sarcolemmal components

Calpain 3 (Capn3) is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. This enigmatic protease has many unique features among the...
Mol. Cell. Biol. - issue: 24 - volume: 23 - pages: 9127-9135.

Magdinier, F.  et al. 2002

Epigenetic marks at BRCA1 and p53 coding sequences in early human embryogenesis

In the vertebrate genome, methylation of deoxycytosine residues of CpGs dinucleotide has been associated with transcriptional silencing of genes, parental imprinting, X-inactivation and chromatin...
Mol. Hum. Reprod. - issue: 7 - volume: 8 - pages: 630-635.

Billard, L.  et al. 2002

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland

During the last years, a direct link between DNA methylation and repressive chromatin structure has been established. This structural modification is mediated by histone deacetylases targeted to the...
Oncogene - issue: 17 - volume: 21 - pages: 2704-2712.

Bachelier, R.  et al. 2002

Retroviral transduction of splice variant Brca1-Delta11 or mutant Brca1-W1777Stop causes mouse epithelial mammary atypical duct hyperplasia

We have investigated the effects of the expression of wild-type and mutant Brca1 alleles on the murine mammary gland morphogenesis and carcinogenesis. Primary cultures of mammary cells from...
Virchows Arch. - issue: 3 - volume: 440 - pages: 261-266.

Gaillard, S.  et al. 2001

Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1

Caveolins are scaffolding proteins able to collect on caveolae a large number of signalling proteins bearing a caveolin-binding motif. The proteins of the striatin family, striatin, SG2NA, and...
FEBS Lett. - issue: 1 - volume: 508 - pages: 49-52.

Bartoli, M.  et al. 2001

Interactions of the rapsyn RING-H2 domain with dystroglycan

Rapsyn, a peripheral membrane protein of skeletal muscle, is necessary for the formation of the highly organized structure of the vertebrate neuromuscular junction. For mice lacking rapsyn, there is a...
J. Biol. Chem. - issue: 27 - volume: 276 - pages: 24911-24917.

Magdinier, F.  et al. 2001

Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia

DNA methylation of tumor suppressor genes is a common feature of human cancer. The cyclin-dependent kinase inhibitor gene p16/Ink4A is hypermethylated in a wide range of malignant tissues and the...
Proc. Natl. Acad. Sci. U.S.A. - issue: 9 - volume: 98 - pages: 4990-4995.

Magdinier, F.  et al. 2000

Regional methylation of the 5' end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells

In mammalians, demethylation of specific promoter regions often correlates with gene activation; inversely, dense methylation of CpG islands leads to gene silencing, probably mediated by methyl-CpG...
FASEB J. - issue: 11 - volume: 14 - pages: 1585-1594.

Bartoli, M.  et al. 1999

Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity

Striatin, an intraneuronal, calmodulin-binding protein addressed to dendrites and spines, is expressed in the motor system, particularly the striatum and motoneurons. Striatin contains a high number...
J. Neurobiol. - issue: 2 - volume: 40 - pages: 234-243.

Magdinier, F.  et al. 1999

BRCA1 expression during prenatal development of the human mammary gland

Germ-line alterations of BRCA1 are associated with elevated risk of breast cancer. Evidence for the involvement of Brca1 in cellular differentiation and morphogenesis has been obtained in mouse models...
Oncogene - issue: 27 - volume: 18 - pages: 4039-4043.

Magdinier, F.  et al. 1998

Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region

Germ-line alterations of BRCA1 are responsible for about 50% of familial breast cancers. Although its biological function(s) has not yet been fully determined, it has been suggested that it may act as...
Oncogene - issue: 24 - volume: 17 - pages: 3169-3176.

Bartoli, M.  et al. 1998

Interaction of calmodulin with striatin, a WD-repeat protein present in neuronal dendritic spines

Rat striatin, a quantitatively minor protein belonging to the WD-repeat family of proteins, is a Ca2+/calmodulin-binding protein mostly expressed in the striatum and in the motor and olfactory systems...
J. Biol. Chem. - issue: 35 - volume: 273 - pages: 22248-22253.

Salin, P.  et al. 1998

Distribution of striatin, a newly identified calmodulin-binding protein in the rat brain: an in situ hybridization and immunocytochemical study

Striatin, a 110-kDa protein, is the first member of the tryptophane-aspartate repeat protein family known to bind calmodulin in the presence of Ca2+. We examined the distribution of striatin and its...
J. Comp. Neurol. - issue: 1 - volume: 397 - pages: 41-59.

Moqrich, A.  et al. 1998

Cloning of human striatin cDNA (STRN), gene mapping to 2p22-p21, and preferential expression in brain

Rat striatin, a recently discovered calmodulin-binding protein belonging to the WD repeat family, is expressed in neurons, mostly in the striatum and motor and olfactory systems. Striatin is localized...
Genomics - issue: 1 - volume: 51 - pages: 136-139.

Kachidian, P.  et al. 1998

Relationships between striatin-containing neurons and cortical or thalamic afferent fibres in the rat striatum. An ultrastructural study by dual labelling

Striatin, a recently isolated rat brain calmodulin-binding protein belonging to the WD-repeat protein family, is thought to be part of a calcium signal transduction pathway presumably specific to...
Neuroscience - issue: 1 - volume: 85 - pages: 111-122.

Ribieras, S.  et al. 1997

Abundance of BRCA1 transcripts in human cancer and lymphoblastoid cell lines carrying BRCA1 germ-line alterations

A competitive polymerase chain reaction has been developed for quantitation of BRCA1 mRNA. In human cancer cell lines, the amount of BRCA1 mRNA is relatively low, ranging from 6 to 38 copies per cell....
Int. J. Cancer - issue: 5 - volume: 73 - pages: 715-718.

Castets, F.  et al. 1996

A novel calmodulin-binding protein, belonging to the WD-repeat family, is localized in dendrites of a subset of CNS neurons

A rat brain synaptosomal protein of 110,000 M(r) present in a fraction highly enriched in adenylyl cyclase activity was microsequenced (Castets, F., G. Baillat, S. Mirzoeva, K. Mabrouk, J. Garin, J....
J. Cell Biol. - issue: 4 - volume: 134 - pages: 1051-1062.