المؤلفون: Camille Laberthonnière, Elva‐Maria Novoa‐del‐Toro, Mégane Delourme, Raphaël Chevalier, Natacha Broucqsault, Kilian Mazaleyrat, Nathalie Streichenberger, Véronique Manel, Rafaëlle Bernard, Emmanuelle Salort Campana, Shahram Attarian, Karine Nguyen, Jérôme D. Robin, Anais Baudot, Frédérique Magdinier

المصدر: Journal of Cachexia, Sarcopenia and Muscle, Vol 13, Iss 1, Pp 621-635 (2022)

مصطلحات موضوعية: Facioscapulohumeral dystrophy, Induced pluripotent stem cells, System biology, Pathophysiology, Sarcomere, Muscle contraction, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695

الوصف: Abstract Background Facioscapulohumeral dystrophy (FSHD) is a late‐onset autosomal dominant form of muscular dystrophy involving specific groups of muscles with variable weakness that precedes inflammatory response, fat infiltration, and muscle atrophy. As there is currently no cure for this disease, understanding and modelling the typical muscle weakness in FSHD remains a major milestone towards deciphering the disease pathogenesis as it will pave the way to therapeutic strategies aimed at correcting the functional muscular defect in patients. Methods To gain further insights into the specificity of the muscle alteration in this disease, we derived induced pluripotent stem cells from patients affected with Types 1 and 2 FSHD but also from patients affected with Bosma arhinia and microphthalmia. We differentiated these cells into contractile innervated muscle fibres and analysed their transcriptome by RNA Seq in comparison with cells derived from healthy donors. To uncover biological pathways altered in the disease, we applied MOGAMUN, a multi‐objective genetic algorithm that integrates multiplex complex networks of biological interactions (protein–protein interactions, co‐expression, and biological pathways) and RNA Seq expression data to identify active modules. Results We identified 132 differentially expressed genes that are specific to FSHD cells (false discovery rate

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2190-5991Test; https://doaj.org/toc/2190-6009Test

الوصول الحر: https://doaj.org/article/8f932ee1e4384c53a16531a5f4c02563Test

المؤلفون: Camille Laberthonnière, Elva Maria Novoa-del-Toro, Raphaël Chevalier, Natacha Broucqsault, Vanitha Venkoba Rao, Jean Philippe Trani, Karine Nguyen, Shifeng Xue, Bruno Reversade, Jérôme D. Robin, Anais Baudot, Frédérique Magdinier

المصدر: Biomedicines, Vol 9, Iss 7, p 751 (2021)

مصطلحات موضوعية: SMCHD1, Bosma Arhinia and Microphthalmia Syndrome, Facio Scapulo Humeral Dystrophy, RNA-Seq, neural crest stem cells, induced pluripotent stem cells, Biology (General), QH301-705.5

الوصف: Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation–migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2227-9059/9/7/751Test; https://doaj.org/toc/2227-9059Test

الوصول الحر: https://doaj.org/article/a79f48bb80374f30b99138b221ba7b8eTest

المؤلفون: Kilian Mazaleyrat, Cherif Badja, Natacha Broucqsault, Raphaël Chevalier, Camille Laberthonnière, Camille Dion, Lyla Baldasseroni, Claire El-Yazidi, Morgane Thomas, Richard Bachelier, Alexandre Altié, Karine Nguyen, Nicolas Lévy, Jérôme D. Robin, Frédérique Magdinier

المصدر: Cells, Vol 9, Iss 6, p 1531 (2020)

مصطلحات موضوعية: human induced pluripotent cells, differentiation, myoblasts, myotubes, motor neurons, satellite cells, Cytology, QH573-671

الوصف: Induced pluripotent stem cells (iPSCs) obtained by reprogramming primary somatic cells have revolutionized the fields of cell biology and disease modeling. However, the number protocols for generating mature muscle fibers with sarcolemmal organization using iPSCs remain limited, and partly mimic the complexity of mature skeletal muscle. Methods: We used a novel combination of small molecules added in a precise sequence for the simultaneous codifferentiation of human iPSCs into skeletal muscle cells and motor neurons. Results: We show that the presence of both cell types reduces the production time for millimeter-long multinucleated muscle fibers with sarcolemmal organization. Muscle fiber contractions are visible in 19–21 days, and can be maintained over long period thanks to the production of innervated multinucleated mature skeletal muscle fibers with autonomous cell regeneration of PAX7-positive cells and extracellular matrix synthesis. The sequential addition of specific molecules recapitulates key steps of human peripheral neurogenesis and myogenesis. Furthermore, this organoid-like culture can be used for functional evaluation and drug screening. Conclusion: Our protocol, which is applicable to hiPSCs from healthy individuals, was validated in Duchenne Muscular Dystrophy, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy and type 2A Limb-Girdle Muscular Dystrophy, opening new paths for the exploration of muscle differentiation, disease modeling and drug discovery.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2073-4409/9/6/1531Test; https://doaj.org/toc/2073-4409Test

الوصول الحر: https://doaj.org/article/8d061bb2ffea436e998913b85cd1c2afTest

المؤلفون: Amina Boussouar, Caroline Barette, Robert Nadon, Adelaïde Saint-Léger, Natacha Broucqsault, Alexandre Ottaviani, Arva Firozhoussen, Yiming Lu, Laurence Lafanechère, Eric Gilson, Frédérique Magdinier, Jing Ye

المصدر: Molecular Therapy: Nucleic Acids, Vol 2, Iss C (2013)

مصطلحات موضوعية: DNA damage response, flavanoid, polyphenol, telomere, telomeric position effect, telomere-induced foci, Therapeutics. Pharmacology, RM1-950

الوصف: 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 identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in human cells. We further investigated their influence on telomere integrity and showed that both drugs drastically deprotect telomeres against DNA damage response. However, telomere deprotection triggered by shelterin dysfunction does not affect TPE, indicating that acacetin and chrysin target several functions of telomeres. These results show that TPE-based screening assays represent valuable methods to discover new compounds targeting telomeres.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2162253116301743Test; https://doaj.org/toc/2162-2531Test

الوصول الحر: https://doaj.org/article/236524645f794b94a7fa5a681cdfde93Test

المؤلفون: Bruno Reversade, Anaïs Baudot, Jean Philippe Trani, Frédérique Magdinier, Shifeng Xue, Karine Nguyen, Jérôme D. Robin, Vanitha Venkoba Rao, Elva Maria Novoa-Del-Toro, Camille Laberthonnière, Raphaël Chevalier, Natacha Broucqsault

المساهمون: Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Reversade, Bruno, Laberthonnière, C., Novoa-Del-Toro, E. M., Chevalier, R., Broucqsault, N., Rao, V. V., Trani, J. P., Nguyen, K., Xue, S., Robin, J. D., Baudot, A., Magdinier, F., School of Medicine, ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development

المصدر: Biomedicines
Volume 9
Issue 7
Biomedicines, MDPI, 2021, 9 (7), pp.751. ⟨10.3390/biomedicines9070751⟩
Biomedicines, Vol 9, Iss 751, p 751 (2021)
Biomedicines, 2021, 9 (7), pp.751. ⟨10.3390/biomedicines9070751⟩
Biomedicines, 9(7):751. MDPI AG

مصطلحات موضوعية: QH301-705.5, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Biology, medicine.disease_cause, Microphthalmia, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, RNA-Seq, Biology (General), Induced pluripotent stem cell, Protein kinase B, Biochemistry, Molecular biology, Research and experimental medicine, Pharmacology, Pharmacy, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bosma Arhinia and Microphthalmia Syndrome, SMCHD1, Neural crest, medicine.disease, Phenotype, Cell biology, Induced pluripotent stem cells, Facio Scapulo Humeral Dystrophy, RNA-Seqneural crest stem cells, Systems biology, Stem cell, Neural crest stem cells, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology

الوصف: Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation-migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.
Marseille Maladies Rares (MarMaRa) Institute French Investissement D’avenir Programme; NUS PYP Start-up Grant; Association Française contre les Myopathies; Fondation Maladies Rares; French Ministry of Education Fellowship; FSH Society; Excellence Initiative of Aix-Marseille University A*Midex; National Research Foundation; Branco Weiss Foundation; EMBO Young Investigator; Agency for Science & Technology and Research (A*STAR) Use-Inspired Basic Research (UIBR) Grant

وصف الملف: application/pdf; text/academic publication

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0adb94ab76a315ee460ccb96f965a57bTest
http://www.scopus.com/inward/record.url?scp=85109493277&partnerID=8YFLogxKTest

المؤلفون: Mégane, Delourme, Natacha, Broucqsault, Kilian, Mazaleyrat, Frédérique, Magdinier

المصدر: Methods in molecular biology (Clifton, N.J.). 2454

مصطلحات موضوعية: Motor Neurons, Induced Pluripotent Stem Cells, Muscle Fibers, Skeletal, Humans, Cell Differentiation, Muscle, Skeletal, Cells, Cultured, Muscle Contraction

الوصف: Only a limited number of large-scale protocols describe the production of mature skeletal muscle fibers from human induced pluripotent stem cells (hiPSCs). Here we describe a novel procedure for simultaneous differentiation of hiPSC into muscle cells and motor neurons, that generates innervated and contractile multinucleated skeletal muscle fibers with sarcomeric organization. Our protocol permits the production of expandable skeletal muscle progenitor cells and mature skeletal muscle fibers that can be used for the exploration of skeletal muscle differentiation for basic research, disease modeling, and drug discovery.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::4d87a69b564bb2598ddc6852dbab75b9Test
https://pubmed.ncbi.nlm.nih.gov/33368020Test

المؤلفون: Kilian Mazaleyrat, Frédérique Magdinier, Natacha Broucqsault, Mégane Delourme

المساهمون: Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gall, Valérie

المصدر: Methods in Molecular Biology
Methods in Molecular Biology, 2020, ⟨10.1007/7651_2020_334⟩
Methods in Molecular Biology ISBN: 9781071621189

مصطلحات موضوعية: 0301 basic medicine, [SDV]Life Sciences [q-bio], Neuromuscular junction, Stem cells, Biology, Sarcomere, Myoblasts, 03 medical and health sciences, 0302 clinical medicine, Multinucleate, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Myocyte, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neuromuscular disease modeling, Progenitor cell, Motor neurons, Muscle fiber, Contraction, Myogenesis, Skeletal muscle, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Myotubes, Stem cell, 030217 neurology & neurosurgery

الوصف: International audience; Only a limited number of large-scale protocols describe the production of mature skeletal muscle fibers from human induced pluripotent stem cells (hiPSCs). Here we describe a novel procedure for simultaneous differentiation of hiPSC into muscle cells and motor neurons, that generates innervated and contractile multinucleated skeletal muscle fibers with sarcomeric organization. Our protocol permits the production of expandable skeletal muscle progenitor cells and mature skeletal muscle fibers that can be used for the exploration of skeletal muscle differentiation for basic research, disease modeling, and drug discovery.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be041b29c98568851b8f97410099a7beTest
https://hal-amu.archives-ouvertes.fr/hal-03142891Test

المؤلفون: Camille Laberthonnière, Marie-Cécile Gaillard, Natacha Broucqsault, Cherif Badja, Stéphane Roche, Jérôme D. Robin, Julia Morere, Karine Nguyen, Frédérique Magdinier, Camille Dion

المساهمون: Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

المصدر: Scientific Reports
Scientific Reports, Nature Publishing Group, 2019, ⟨10.1038/s41598-019-46861-x⟩
Scientific Reports, 2019, 1, ⟨10.1038/s41598-019-46861-x⟩
Scientific Reports, Vol 9, Iss 1, Pp 1-15 (2019)

مصطلحات موضوعية: Male, Chromosomal Proteins, Non-Histone, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, lcsh:Medicine, Diseases, Pathogenesis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 0302 clinical medicine, Gene expression, lcsh:Science, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Middle Aged, Cadherins, Subtelomere, Chromatin, Muscular Dystrophy, Facioscapulohumeral, Epigenetics, Female, Chromosomes, Human, Pair 4, Adult, Adolescent, Induced Pluripotent Stem Cells, Locus (genetics), Biology, Chromatin structure, Article, Young Adult, 03 medical and health sciences, Imaging, Three-Dimensional, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Muscle, Skeletal, Gene, Aged, 030304 developmental biology, lcsh:R, Infant, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fibroblasts, Chromosome 4, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Mutation, lcsh:Q, 030217 neurology & neurosurgery

الوصف: International audience; 1 Facio-Scapulo Humeral dystrophy (FSHD) is the third most common myopathy, affecting 1 amongst 10,000 individuals (FSHD1, OMIM #158900). This autosomal dominant pathology is associated in 95% of cases with genetic and epigenetic alterations in the subtelomeric region at the extremity of the long arm of chromosome 4 (q arm). A large proportion of the remaining 5% of cases carry a mutation in the SMCHD1 gene (FSHD2, OMIM #158901). Here, we explored the 3D organization of the 4q35 locus by three-dimensions DNA in situ fluorescent hybridization (3D-FISH) in primary fibroblasts isolated from patients and healthy donors. We found that D4Z4 contractions and/or SMCHD1 mutations impact the spatial organization of the 4q35 region and trigger changes in the expression of different genes. Changes in gene expression were corroborated in muscle biopsies suggesting that the modified chromatin landscape impelled a modulation in the level of expression of a number of genes across the 4q35 locus in FSHD. Using induced pluripotent stem cells (hIPSC), we further examined whether chromatin organization is inherited after reprogramming or acquired during differentiation and showed that folding of the 4q35 region is modified upon differentiation. These results together with previous findings highlight the role of the D4Z4 macrosatellite repeat in the topological organization of chromatin and further indicate that the D4Z4-dependent 3D structure induces transcriptional changes of 4q35 genes expression.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5bd636a86000d8f6d6952d1613d637c7Test
https://hal.archives-ouvertes.fr/hal-01951503v2/documentTest

المؤلفون: Camille Dion, Stéphane Roche, Camille Laberthonnière, Natacha Broucqsault, Virginie Mariot, Shifeng Xue, Alexandra D Gurzau, Agnieszka Nowak, Christopher T Gordon, Marie-Cécile Gaillard, Claire El-Yazidi, Morgane Thomas, Andrée Schlupp-Robaglia, Chantal Missirian, Valérie Malan, Liham Ratbi, Abdelaziz Sefiani, Bernd Wollnik, Bernard Binetruy, Emmanuelle Salort Campana, Shahram Attarian, Rafa

المصدر: Nucleic Acids Research

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=r3c4b2081b22::695ed91050c08f577800232398c4d599Test

المؤلفون: Vincent Tiffreau, Albert David, Jon Andoni Urtizberea, Charlene Chaix, Emmanuelle Salort-Campana, Rafaëlle Bernard, Sabrina Sacconi, Karine Nguyen, André Mégarbané, Fabien Zagnoli, Natacha Broucqsault, Jérôme D. Robin, Shahram Attarian, Frédérique Magdinier, Jean-Marie Cuisset, Véronique Manel, Laurene Gerard, Bruno Eymard, Stéphane Roche, Catherine Vovan, Mélanie Fradin, Nicolas Lévy, Christine Barnerias, Rémi Bellance

المساهمون: Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], MLab, Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service epilepsie sommeil et explorations fonctionnelles neuropédiatriques (HFME), Hospices Civils de Lyon (HCL)-Université de Lyon, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Activité Physique, Muscle, Santé (EA4488), Université de Lille, Droit et Santé, Service de Neurologie [Brest], Hôpital d'Instruction des Armées 'Clermont-Tonnerre' (HIA), Maladies Neuromusculaires de l'Enfant, Hôpital Roger Salengro [Lille], Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Roche, Stephane, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)

المصدر: Journal of Medical Genetics
Journal of Medical Genetics, In press, ⟨10.1136/jmedgenet-2018-105949⟩
Journal of Medical Genetics, BMJ Publishing Group, In press, ⟨10.1136/jmedgenet-2018-105949⟩

مصطلحات موضوعية: 0301 basic medicine, Genotype, Genetic counseling, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Locus (genetics), Biology, subtelomeres, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Homology (biology), 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene duplication, molecular combing, smchd1, Genetics, Humans, Genetic Predisposition to Disease, Genetics (clinical), Alleles, Genetic Association Studies, Chromosomes, Human, Pair 10, Haplotype, facio scapulo humeral dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Telomere, Subtelomere, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chromosome Deletion, Chromosomes, Human, Pair 4, 030217 neurology & neurosurgery

الوصف: BackgroundSubtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the SMCHD1 gene. We also recently described patients carrying a complex rearrangement consisting of a cis-duplication of the distal 4q35 locus identified by molecular combing.MethodsUsing this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.ResultsOur analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.ConclusionOverall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91b6d947b729bafe9ca7dad31ad10ddbTest
https://pubmed.ncbi.nlm.nih.gov/31010831Test