A5007803341- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Muscle Physiology and Disorders
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genomics and Rare Diseases
- Genetics and Neurodevelopmental Disorders
- Fungal and yeast genetics research
- Genetic factors in colorectal cancer
- RNA Research and Splicing
- Connective tissue disorders research
- Lysosomal Storage Disorders Research
- Hereditary Neurological Disorders
- Ubiquitin and proteasome pathways
- Oral Health Pathology and Treatment
- Cardiovascular Effects of Exercise
- RNA regulation and disease
- Pharmacological Effects and Toxicity Studies
- Wireless Body Area Networks
- Systemic Sclerosis and Related Diseases
- Phosphodiesterase function and regulation
- HIV/AIDS drug development and treatment
- RNA modifications and cancer
- Nanopore and Nanochannel Transport Studies
- Molecular Biology Techniques and Applications
Inserm
2011-2024
Sorbonne Université
2017-2024
Centre de Recherche en Myologie
2017-2024
Institut de Myologie
2019-2024
Délégation Paris 5
2014-2019
Sorbonne Paris Cité
2014-2019
Université Paris Cité
2009-2019
Institut des Maladies Génétiques Imagine
2014-2019
Hospital for Sick Children
2012-2017
Instituto Nacional de Neurología y Neurocirugía
2013
Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute ongoing disease progression through an affected individual's life with Huntington's or myotonic dystrophy. Broad ranges repeat instability arise between individuals expanded repeats, suggesting the existence modifiers instability. Mice show variable levels depending upon mouse strain. However, date genetic underlying these differences have not been identified. We that liver and striatum R6/1 (HD)...
Myotonic dystrophy (DM1) affects multiple organs, shows age-dependent progression and is caused by CTG expansions at the DM1 locus. We determined CpG methylation profile length in tissues from foetuses, adults, non-affected individuals transgenic mice. Analysis included CTCF binding sites upstream downstream of tract, as methylation-sensitive chromatinization transcription In humans, a given foetus, were largest heart smallest liver, differing 40-400 repeats; cerebral cortex cerebellum, up...
Myotonic dystrophy type 1 (DM1) is associated with one of the most highly unstable CTG•CAG repeat expansions. The formation further expansions in transgenic mice carrying expanded tracts requires mismatch repair (MMR) proteins MSH2 and MSH3, forming MutSβ complex. It has been proposed that binding to CAG hairpins blocks its ATPase activity compromising hairpin repair, thereby causing This would suggest binding, but not ATP hydrolysis, by critical for trinucleotide However, it unknown if...
CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, almost exclusive maternal transmission. The correlation between CDM1 expansion size is not absolute, suggesting contributions other factors. We determined CpG methylation flanking 79 blood samples from 20 CDM1-affected individuals; 21, 27, 11 individuals but (henceforth non-CDM1) maternal,...
Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion located in the 3′ UTR of DMPK gene. Expanded transcripts aggregate into nuclear foci and alter function RNA-binding proteins, leading to defects alternative splicing numerous pre-mRNAs. To date, there no curative treatment for DM1. Here we investigated gene-editing strategy using CRISPR-Cas9 system from Staphylococcus aureus (Sa) delete repeats human locus. Co-expression SaCas9 selected pairs single-guide RNAs (sgRNAs)...
Myotonic dystrophy type 1 (DM1) is the most complex and variable trinucleotide repeat disorder caused by an unstable CTG expansion, reaching up to 4000 in severe cases. The genetic clinical variability of DM1 depend on sex age transmitting parent, but also number, presence interruptions and/or degree somatic instability. Currently, it difficult simultaneously accurately determine these contributing factors patients due limitations gold standard methods used molecular diagnostics research...
Expansion of CAG/CTG trinucleotide repeats causes numerous inherited neurological disorders, including Huntington's disease (HD), several spinocerebellar ataxias and myotonic dystrophy type 1. Expanded are genetically unstable with a propensity to further expand when transmitted from parents offspring. For many alleles expanded repeats, extensive somatic mosaicism has been documented. CAG repeat diseases, dramatic instability documented in the striatum, larger expansions noted advancing age....
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 caused by an unstable CTG repeat expansion that usually increases in successive generations tissues. family pedigrees have shown ∼90% 10% transmissions result expansions contractions the repeat, respectively. To date, mechanisms contraction remain poorly documented DM1. In this report, we identified two new families apparent no worsening three maternal...
Myotonic dystrophy type 1 (DM1) exhibits highly heterogeneous clinical manifestations caused by an unstable CTG repeat expansion reaching up to 4000 CTG. The variability depends on number, CNG interruptions, and somatic mosaicism. Currently, none of these factors are simultaneously accurately determined due the limitations gold standard methods used in research laboratories. An amplicon method for targeting DMPK locus using single-molecule real-time sequencing was recently developed analyze...
Many human diseases are associated with the abnormal expansion of unstable trinucleotide repeat sequences. The mechanisms size mutation have not been fully dissected, and their understanding must be grounded on detailed analysis distributions in tissues animal models. Small-pool PCR (SP-PCR) is a robust, highly sensitive efficient PCR-based approach to assess levels variation, providing both quantitative qualitative data. method relies amplification very low number DNA molecules, through...
The mismatch repair protein, MSH3, together with MSH2, forms the MutSβ heterodimer which recognizes and repairs base pair mismatches larger insertion/deletion loops in DNA. Lack of specific antibodies against mouse MSH3 has hampered studies its expression localization. Mouse is not immunogenic normal mice. This problem was overcome by immunizing msh3-knockout mice generating a panel ten monoclonal antibodies, two localize specifically cultured cells bind to an epitope containing amino-acids...
Abstract Myotonic dystrophy type 1 (DM1) exhibits highly heterogeneous clinical manifestations caused by an unstable CTG repeat expansion reaching up to 4,000 CTG. The dynamics of repeats and variability depends on the number, CNG interruptions, DNA methylation, somatic mosaicism, but also gene modifiers. Around 10% DM1 population carries triplet interruptions (CCG, CGG, CTC, CAG), which differ in number nature between families. CCG have been associated with stabilization expansions a milder...
ABSTRACT More than 50 repeat expansion disorders have been identified, with long-read sequencing marking a new milestone in the diagnosis of these disorders. Despite major achievements, comprehensive characterization short tandem repeats pathological context remains challenging, primarily due to their inherent characteristics such as motif complexity, high GC content, and variable length. In this study, our aim was thoroughly characterize expansions two neuromuscular diseases: myotonic...
Abstract Trinucleotide repeat expansions are the cause of two dozen neurodegenerative and developmental disorders. One these, myotonic dystrophy type 1 (Steinert disease, or DM1) is due to expansion a CTG triplet in 3’ UTR DMPK gene. We used highly specific DNA endonucleases induce double-strand break tract contract it below pathological length. Expression TALE Nuclease (TALEN) human DM1 cells induced moderate contractions 27% clones analyzed. These exhibited large internal deletions within...
Abstract Myotonic dystrophy type 1 (DM1) exhibits highly heterogeneous clinical manifestations caused by an unstable CTG repeat expansion reaching up to 4,000 CTG. The variability depends on number, CNG interruptions and somatic mosaicism. Currently, none of these factors are simultaneously accurately determined due the limitations gold standard methods used in research laboratories. An amplicon method for targeting DM1 locus using Single-Molecule Real-Time sequencing was recently developed...