المؤلفون: Lee, Young Lim, Bosse, Mirte, Takeda, Haruko, Moreira, Gabriel Costa Monteiro, Karim, Latifa, Druet, Tom, Oget-Ebrad, Claire, Coppieters, Wouter, Veerkamp, Roel F, Groenen, Martien A M, Georges, Michel, Bouwman, Aniek C, Charlier, Carole

المصدر: BMC Genomics, 24 (1), 225 (2023-05-01)

مصطلحات موضوعية: Cattle, Copy number variants, Linkage disequilibrium, Structural variants, Whole genome sequencing, eQTL, POPDC3 protein, human, Muscle Proteins, Cell Adhesion Molecules, Female, Humans, Animals, Genotype, DNA Copy Number Variations, Haplotypes, Polymorphism, Single Nucleotide, Muscle Proteins/genetics, Cell Adhesion Molecules/genetics, Genome, Genomics/methods, Genetics, Biotechnology, Life sciences, Genetics & genetic processes, Sciences du vivant, Génétique & processus génétiques

الوصف: [en] BACKGROUND: Structural variants (SVs) are chromosomal segments that differ between genomes, such as deletions, duplications, insertions, inversions and translocations. The genomics revolution enabled the discovery of sub-microscopic SVs via array and whole-genome sequencing (WGS) data, paving the way to unravel the functional impact of SVs. Recent human expression QTL mapping studies demonstrated that SVs play a disproportionally large role in altering gene expression, underlining the importance of including SVs in genetic analyses. Therefore, this study aimed to generate and explore a high-quality bovine SV catalogue exploiting a unique cattle family cohort data (total 266 samples, forming 127 trios).RESULTS: We curated 13,731 SVs segregating in the population, consisting of 12,201 deletions, 1,509 duplications, and 21 multi-allelic CNVs (> 50-bp). Of these, we validated a subset of copy number variants (CNVs) utilising a direct genotyping approach in an independent cohort, indicating that at least 62% of the CNVs are true variants, segregating in the population. Among gene-disrupting SVs, we prioritised two likely high impact duplications, encompassing ORM1 and POPDC3 genes, respectively. Liver expression QTL mapping results revealed that these duplications are likely causing altered gene expression, confirming the functional importance of SVs. Although most of the accurately genotyped CNVs are tagged by single nucleotide polymorphisms (SNPs) ascertained in WGS data, most CNVs were not captured by individual SNPs obtained from a 50K genotyping array.CONCLUSION: We generated a high-quality SV catalogue exploiting unique whole genome sequenced bovine family cohort data. Two high impact duplications upregulating the ORM1 and POPDC3 are putative candidates for postpartum feed intake and hoof health traits, thus warranting further investigation. Generally, CNVs were in low LD with SNPs on the 50K array. Hence, it remains crucial to incorporate CNVs via means other than tagging SNPs, such as investigation of tagging haplotypes, direct imputation of CNVs, or direct genotyping as done in the current study. The SV catalogue and the custom genotyping array generated in the current study will serve as valuable resources accelerating utilisation of full spectrum of genetic variants in bovine genomes.
Seventh Framework Programme
H2020

العلاقة: https://link.springer.com/content/pdf/10.1186/s12864-023-09259-8.pdfTest; urn:issn:1471-2164

الوصول الحر: https://orbi.uliege.be/handle/2268/303481Test

المؤلفون: Ramirez-Martinez, Andres, Zhang, Yichi, van den Boogaard, Marie-Jose, McAnally, John R, Rodriguez-Caycedo, Cristina, Chai, Andreas C, Chemello, Francesco, Massink, Maarten Pg, Cuppen, Inge, Elferink, Martin G, van Es, Robert Jj, Janssen, Nard G, Walraven-van Oijen, Linda Pam, Liu, Ning, Bassel-Duby, Rhonda, van Jaarsveld, Richard H, Olson, Eric N

المساهمون: Genetica, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Neurologen, Brain, Genetica Medische Informatica, CMM Groep Burgering, Cancer, MS Mondziekten/Kaakchirurgie, Other research (not in main researchprogram)

مصطلحات موضوعية: Animals, Humans, Membrane Proteins/genetics, Mice, Mobius Syndrome, Muscle Proteins/genetics, Muscular Diseases/genetics, Pierre Robin Syndrome, General Medicine, Journal Article

الوصف: Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

وصف الملف: application/pdf

العلاقة: https://dspace.library.uu.nl/handle/1874/446496Test

الإتاحة: https://dspace.library.uu.nl/handle/1874/446496Test

المؤلفون: Erlenhardt, Nadine, Kletke, Olaf, Wohlfarth, Franziska, Komadowski, Marlene A., Clasen, Lukas, Makimoto, Hisaki, Rinné, Susanne, Kelm, Malte, Jungen, Christiane, Decher, Niels, Meyer, Christian, Klöcker, Nikolaj

المصدر: http://lobid.org/resources/99370672927306441Test#!, 472(12):1733-1742.

مصطلحات موضوعية: Bradycardia/physiopathology [MeSH], Action Potentials [MeSH], Heart Rate [MeSH], Mutation, Missense [MeSH], Myocytes, Cardiac/physiology [MeSH], Potassium Channels/metabolism [MeSH], Genetic variant, Bradycardia/diagnosis [MeSH], Ion channels, receptors and transporters, Cardiac/metabolism [MeSH], Sick sinus syndrome, PEX5R, Protein Transport [MeSH], Muscle Proteins/metabolism [MeSH], Muscle Proteins/genetics [MeSH], Female [MeSH], Funny current, Potassium Channels/genetics [MeSH], Humans [MeSH], Bradycardia/genetics [MeSH], Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism [MeSH], Rats [MeSH], Middle Aged [MeSH], Animals [MeSH], Rats, Wistar [MeSH], Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics [MeSH]

الوصف: The hyperpolarization-activated cation current I

العلاقة: https://repository.publisso.de/resource/frl:6467298Test; https://doi.org/10.1007/s00424-020-02481-3Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691308Test/

الإتاحة: https://doi.org/10.1007/s00424-020-02481-3Test
https://repository.publisso.de/resource/frl:6467298Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691308Test/

المؤلفون: Veith, Christine, Neghabian, Dariusch, Luitel, Himal, Wilhelm, Jochen, Egemnazarov, Bakytbek, Muntanjohl, Caja, Fischer, Jan-Hendrik, Dahal, Bhola Kumar, Schermuly, Ralph Theo, Ghofrani, Hossein Ardeschir, Grimminger, Friedrich, Fink, Ludger, Kwapiszewska, Grazyna, Weissmann, Norbert, Sydykov, Akylbek

المصدر: http://lobid.org/resources/99370671625606441Test#!, 115(2):17.

مصطلحات موضوعية: Ventricular Dysfunction, Right/physiopathology [MeSH], Mice, Inbred C57BL [MeSH], Heart Ventricles/physiopathology [MeSH], Original Contribution, LIM Domain Proteins/deficiency [MeSH], Right/pathology [MeSH], Right/genetics [MeSH], Hypertrophy, Right Ventricular/physiopathology [MeSH], Male [MeSH], Natriuretic Peptides/metabolism [MeSH], Four and-a-half LIM domain 1 protein, Calcium-Binding Proteins/metabolism [MeSH], Ryanodine Receptor Calcium Release Channel/metabolism [MeSH], Muscle Proteins/metabolism [MeSH], Disease Models, Animal [MeSH], LIM Domain Proteins/genetics [MeSH], Muscle Proteins/genetics [MeSH], Cytoskeletal proteins, Intracellular Signaling Peptides and Proteins/metabolism [MeSH], Fibrosis [MeSH], Right Ventricular/metabolism [MeSH], Ventricular Function, Right [MeSH], Intracellular Signaling Peptides and Proteins/deficiency [MeSH], Animals [MeSH], Knockout [MeSH]

الوصف: Aims!#!The cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) has recently been identified as a novel key player in pulmonary hypertension as well as in left heart diseases. In this regard, FHL-1 has been implicated in dysregulated hypertrophic signaling in pulmonary arterial smooth muscle cells leading to pulmonary hypertension. In mice, FHL-1-deficiency (FHL-1!##!Methods and results!#!We investigated FHL-1 expression in C57Bl/6 mice subjected to chronic biomechanical stress and found it to be enhanced in the right ventricle (RV). Next, we subjected FHL-1!##!Conclusion!#!FHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.

العلاقة: https://repository.publisso.de/resource/frl:6466416Test; https://doi.org/10.1007/s00395-019-0767-5Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981327Test/

الإتاحة: https://doi.org/10.1007/s00395-019-0767-5Test
https://repository.publisso.de/resource/frl:6466416Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981327Test/

المؤلفون: Regeneron Genetics Center

المساهمون: Onderzoek Precision medicine, Team Medisch, Circulatory Health

مصطلحات موضوعية: Adaptor Proteins, Signal Transducing/genetics, Apoptosis Regulatory Proteins/genetics, Atrial Fibrillation/genetics, Cardiomyopathies/genetics, Carrier Proteins/genetics, Case-Control Studies, Coronary Artery Disease/genetics, Cyclin-Dependent Kinase Inhibitor p21/genetics, Genome-Wide Association Study, Heart Failure/genetics, Humans, Mendelian Randomization Analysis, Microfilament Proteins/genetics, Muscle Proteins/genetics, Risk Factors, Ventricular Function, Left/genetics, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Meta-Analysis, Journal Article

الوصف: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

وصف الملف: application/pdf

العلاقة: https://dspace.library.uu.nl/handle/1874/442049Test

الإتاحة: https://dspace.library.uu.nl/handle/1874/442049Test

المؤلفون: Villar-Quiles, Rocío Nur, Catervi, Fabio, Cabet, Eva, Juntas-Morales, Raul, Genetti, Casie C.A., Gidaro, Teresa, Koparir, Asuman, Yüksel, Adnan, Coppens, Sandra, Deconinck, Nicolas, Pierce-Hoffman, Emma, Lornage, Xavière, Durigneux, Julien, Laporte, Jocelyn, Rendu, John, Romero, Norma Beatriz, Beggs, Alan A.H., Servais, Lara, Cossée, Mireille, Olivé, Montse, Böhm, Johann, Duband-Goulet, Isabelle, Ferreiro, Ana

المصدر: Annals of neurology, 87 (2

مصطلحات موضوعية: Sciences bio-médicales et agricoles, Adult, Amino Acid Transport System y+ -- metabolism -- physiology, Cell Cycle -- physiology, Cells, Cultured, Child, Preschool, Female, Fibroblasts -- physiology, Humans, Infant, Male, Middle Aged, Muscle Proteins -- genetics, Muscle, Skeletal -- pathology -- physiopathology, Muscular Diseases -- genetics -- physiopathology, Mutation, Pedigree, Phenotype, Transcription Factors -- genetics

الوصف: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. ; info:eu-repo/semantics/published

وصف الملف: 1 full-text file(s): application/pdf

العلاقة: uri/info:doi/10.1002/ana.25660; uri/info:pmid/31794073; uri/info:scp/85077147655; uri/info:pmcid/PMC6980348; https://dipot.ulb.ac.be/dspace/bitstream/2013/307754/3/ASC1myopathy-Villar-Quiles.pdfTest; http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/307754Test

الإتاحة: http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/307754Test
https://dipot.ulb.ac.be/dspace/bitstream/2013/307754/3/ASC1myopathy-Villar-Quiles.pdfTest

المساهمون: Sang-Eun Jung, Seung Min Lim, Sae Rom Hong, Eun Hee Lee, Kyoung-Jin Shin, Hwan Young Lee, Shin, Kyoung Jin

مصطلحات موضوعية: Acetyltransferases/genetics, Adolescent, Adult, Aged, Aging/genetics, Blood Chemical Analysis, CpG Islands/genetics, DNA Methylation, Forensic Genetics, Genetic Markers, Genotyping Techniques/instrumentation, Humans, LIM-Homeodomain Proteins/genetics, Membrane Proteins/genetics, Metalloproteins/genetics, Middle Aged, Mouth Mucosa/chemistry, Muscle Proteins/genetics, Saliva/chemistry, Sequence Analysis, DNA, Sp Transcription Factors/genetics, Transcription Factors/genetics, Young Adult, Age, Blood, Buccal swab, DNA methylation, Methylation SNaPshot, Saliva

الوصف: Many studies have reported age-associated DNA methylation changes and age-predictive models in various tissues and body fluids. Although age-associated DNA methylation changes can be tissue-specific, a multi-tissue age predictor that is applicable to various tissues and body fluids with considerable prediction accuracy might be valuable. In this study, DNA methylation at 5 CpG sites from the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C, and TRIM59 genes were investigated in 448 samples from blood, saliva, and buccal swabs. A multiplex methylation SNaPshot assay was developed to measure DNA methylation simultaneously at the 5 CpG sites. Among the 5 CpG sites, 3 CpG sites in the ELOVL2, KLF14 and TRIM59 genes demonstrated strong correlation between DNA methylation and age in all 3 sample types. Age prediction models built separately for each sample type using the DNA methylation values at the 5 CpG sites showed high prediction accuracy with a Mean Absolute Deviation from the chronological age (MAD) of 3.478 years in blood, 3.552 years in saliva and 4.293 years in buccal swab samples. A tissue-combined model constructed with 300 training samples including 100 samples from each blood, saliva and buccal swab samples demonstrated a very strong correlation between predicted and chronological ages (r = 0.937) and a high prediction accuracy with a MAD of 3.844 years in the 148 independent test set samples of 50 blood, 50 saliva and 48 buccal swab samples. Although more validation might be needed, the tissue-combined model's prediction accuracies in each sample type were very much similar to those obtained from each tissue-specific model. The multiplex methylation SNaPshot assay and the age prediction models in our study would be useful in forensic analysis, which frequently involves DNA from blood, saliva, and buccal swab samples. ; restriction

العلاقة: FORENSIC SCIENCE INTERNATIONAL-GENETICS; J00905; OAK-2019-01266; https://ir.ymlib.yonsei.ac.kr/handle/22282913/169896Test; https://www.sciencedirect.com/science/article/pii/S1872497318302382Test; T201901477; FORENSIC SCIENCE INTERNATIONAL-GENETICS, Vol.38 : 1-8, 2019; 62882

الإتاحة: https://doi.org/10.1016/j.fsigen.2018.09.010Test
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169896Test
https://www.sciencedirect.com/science/article/pii/S1872497318302382Test

المؤلفون: Hoffmann, C, Mao, X, Brown-Clay, J, Moreau, F, Al Absi, A, Wurzer, H, Sousa, B, Schmitt, F, Berchem, G, Janji, B, Thomas, C

المساهمون: Instituto de Investigação e Inovação em Saúde

مصطلحات موضوعية: Adult, Aged, Animals, Breast / pathology, Breast Neoplasms / genetics, Breast Neoplasms / mortality, Breast Neoplasms / pathology, Cell Hypoxia, Cell Line, Tumor, Cell Movement, Extracellular Matrix / pathology, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Hypoxia-Inducible Factor 1, alpha Subunit / genetics, alpha Subunit / metabolism, Kaplan-Meier Estimate, LIM Domain Proteins / genetics, LIM Domain Proteins / metabolism, Mice, Middle Aged, Muscle Proteins / genetics, Muscle Proteins / metabolismo, Neoplasm Invasiveness / pathology, Nuclear Proteins / genetics, Nuclear Proteins / metabolismo

الوصف: Hypoxia is a common feature of solid tumours that promotes invasion and metastatic dissemination. Invadopodia are actin-rich membrane protrusions that direct extracellular matrix proteolysis and facilitate tumour cell invasion. Here, we show that CSRP2, an invadopodial actin bundling protein, is upregulated by hypoxia in various breast cancer cell lines, as well as in pre-clinical and clinical breast tumour specimens. We functionally characterized two hypoxia responsive elements within the proximal promoter of CSRP2 gene which are targeted by hypoxia-inducible factor-1 (HIF-1) and required for promoter transactivation in response to hypoxia. Remarkably, CSRP2 knockdown significantly inhibits hypoxia-stimulated invadopodium formation, ECM degradation and invasion in MDA-MB-231 cells, while CSRP2 forced expression was sufficient to enhance the invasive capacity of HIF-1a-depleted cells under hypoxia. In MCF-7 cells, CSRP2 upregulation was required for hypoxia-induced formation of invadopodium precursors that were unable to promote ECM degradation. Collectively, our data support that CSRP2 is a novel and direct cytoskeletal target of HIF-1 which facilitates hypoxia-induced breast cancer cell invasion by promoting invadopodia formation. ; The authors are grateful to Monika Dieterle, Arnaud Muller, Pter Nazarov and Muhammad Zaeem Noman (Oncology Department, LIH, Luxembourg) for technical assistance, support in statistical analyses and constructive discussions. The authors also warmly thank Sara A. Courtneidge for the gift of the Tks5-GFP construct (Oregon Health and Science University, Portland, USA). This work was mainly supported by a research grant from “Fondation Cancer” Luxembourg (FC/2016/02), and the National Research Fund (C16/ BM/11297905). Joshua Brown Clay is recipient of a Postdoctoral fellowship from “Fonds De La Recherche Scientifque” - FNRS “Télévie” (7.4512.16). Antoun Al Absi and Hannah Wurzer are recipients of PhD fellowships from the National Research Fund, Luxembourg (AFR7892325 and ...

وصف الملف: application/pdf

العلاقة: Scientific Reports, vol.8(1):10191; https://www.nature.com/articles/s41598-018-28637-xTest; https://hdl.handle.net/10216/127417Test

الإتاحة: https://doi.org/10.1038/s41598-018-28637-xTest
https://hdl.handle.net/10216/127417Test

المؤلفون: Fransson, Dan, Nielsen, Tobias Schmidt, Olsson, Karl, Christensson, Tobias, Bradley, Paul S, Fatouros, Ioannis G, Krustrup, Peter, Nordsborg, Nikolai Baastrup, Mohr, Magni

المصدر: Fransson , D , Nielsen , T S , Olsson , K , Christensson , T , Bradley , P S , Fatouros , I G , Krustrup , P , Nordsborg , N B & Mohr , M 2018 , ' Skeletal muscle and performance adaptations to high-intensity training in elite male soccer players : speed endurance runs versus small-sided game training ' , European Journal of Applied Physiology , vol. 118 , no. 1 , pp. 111-121 . https://doi.org/10.1007/s00421-017-3751-5Test

مصطلحات موضوعية: Adaptation, Physiological, High-Intensity Interval Training/adverse effects, Humans, Male, Muscle Proteins/genetics, Muscle, Skeletal/metabolism, Physical Endurance, Soccer/physiology, Young Adult

الوصف: PURPOSE: To examine the skeletal muscle and performance responses across two different exercise training modalities which are highly applied in soccer training. METHODS: Using an RCT design, 39 well-trained male soccer players were randomized into either a speed endurance training (SET; n = 21) or a small-sided game group (SSG; n = 18). Over 4 weeks, thrice weekly, SET performed 6-10 × 30-s all-out runs with 3-min recovery, while SSG completed 2 × 7-9-min small-sided games with 2-min recovery. Muscle biopsies were obtained from m. vastus lateralis pre and post intervention and were subsequently analysed for metabolic enzyme activity and muscle protein expression. Moreover, the Yo-Yo Intermittent Recovery level 2 test (Yo-Yo IR2) was performed. RESULTS: Muscle CS maximal activity increased (P < 0.05) by 18% in SET only, demonstrating larger (P < 0.05) improvement than SSG, while HAD activity increased (P < 0.05) by 24% in both groups. Na+-K+ ATPase α1 subunit protein expression increased (P < 0.05) in SET and SSG (19 and 37%, respectively), while MCT4 protein expression rose (P < 0.05) by 30 and 61% in SET and SSG, respectively. SOD2 protein expression increased (P < 0.05) by 28 and 37% in SET and SSG, respectively, while GLUT-4 protein expression increased (P < 0.05) by 40% in SSG only. Finally, SET displayed 39% greater improvement (P < 0.05) in Yo-Yo IR2 performance than SSG. CONCLUSION: Speed endurance training improved muscle oxidative capacity and exercise performance more pronouncedly than small-sided game training, but comparable responses were in muscle ion transporters and antioxidative capacity in well-trained male soccer players.

وصف الملف: application/pdf

العلاقة: https://portal.findresearcher.sdu.dk/da/publications/8fa756af-5a12-4d59-89ce-7d0a847c5cc0Test

الإتاحة: https://doi.org/10.1007/s00421-017-3751-5Test
https://portal.findresearcher.sdu.dk/da/publications/8fa756af-5a12-4d59-89ce-7d0a847c5cc0Test

المؤلفون: Johnson, Katherine, Bertoli, Marta, Phillips, Lauren, Töpf, Ana, Van den Bergh, Peter, Vissing, John, Witting, Nanna, Nafissi, Shahriar, Jamal-Omidi, Shirin, Łusakowska, Anna, Kostera-Pruszczyk, Anna, Potulska-Chromik, Anna, Deconinck, Nicolas, Wallgren-Pettersson, Carina, Strang-Karlsson, Sonja, Colomer, Jaume, Claeys, Kristl G, De Ridder, Willem, Baets, Jonathan, von der Hagen, Maja, Fernández-Torrón, Roberto, Zulaica Ijurco, Miren, Espinal Valencia, Juan Bautista, Hahn, Andreas, Durmus, Hacer, Willis, Tracey, Xu, Liwen, Valkanas, Elise, Mullen, Thomas E, Lek, Monkol, MacArthur, Daniel G, Straub, Volker

المصدر: Johnson , K , Bertoli , M , Phillips , L , Töpf , A , Van den Bergh , P , Vissing , J , Witting , N , Nafissi , S , Jamal-Omidi , S , Łusakowska , A , Kostera-Pruszczyk , A , Potulska-Chromik , A , Deconinck , N , Wallgren-Pettersson , C , Strang-Karlsson , S , Colomer , J , Claeys , K G , De Ridder , W , Baets , J , von der Hagen , M , Fernández-Torrón , R , Zulaica Ijurco , M , Espinal Valencia , J ....

مصطلحات موضوعية: Adolescent, Adult, Aged, 80 and over, Child, Preschool, Dystroglycans/metabolism, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins/genetics, Muscular Dystrophies, Limb-Girdle/genetics, Mutation, Phenotype, Whole Exome Sequencing/methods, Young Adult

الوصف: BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration. METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants. RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase. CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

وصف الملف: application/pdf

الإتاحة: https://doi.org/10.1186/s13395-018-0170-1Test
https://curis.ku.dk/portal/da/publications/detection-of-variants-in-dystroglycanopathyassociated-genes-through-the-application-of-targeted-wholeexome-sequencing-analysis-to-a-large-cohort-of-patients-with-unexplained-limbgirdleTest-muscle-weakness(0068e518-f9ce-4b5f-b7f2-313ed225bc7e).html
https://curis.ku.dk/ws/files/218088378/s13395_018_0170_1.pdfTest