8 results on '"Gurzau, Alexandra D."'
Search Results
2. SMCHD1 is involved inde novomethylation of theDUX4-encoding D4Z4 macrosatellite
- Author
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Dion, Camille, primary, Roche, Stéphane, additional, Laberthonnière, Camille, additional, Broucqsault, Natacha, additional, Mariot, Virginie, additional, Xue, Shifeng, additional, Gurzau, Alexandra D, additional, Nowak, Agnieszka, additional, Gordon, Christopher T, additional, Gaillard, Marie-Cécile, additional, El-Yazidi, Claire, additional, Thomas, Morgane, additional, Schlupp-Robaglia, Andrée, additional, Missirian, Chantal, additional, Malan, Valérie, additional, Ratbi, Liham, additional, Sefiani, Abdelaziz, additional, Wollnik, Bernd, additional, Binetruy, Bernard, additional, Salort Campana, Emmanuelle, additional, Attarian, Shahram, additional, Bernard, Rafaelle, additional, Nguyen, Karine, additional, Amiel, Jeanne, additional, Dumonceaux, Julie, additional, Murphy, James M, additional, Déjardin, Jérôme, additional, Blewitt, Marnie E, additional, Reversade, Bruno, additional, Robin, Jérôme D, additional, and Magdinier, Frédérique, additional
- Published
- 2019
- Full Text
- View/download PDF
3. De Novo Mutations In Smchd1 Cause Bosma Arhinia Microphthalmia Syndrome And Abrogate Nasal Development
- Author
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Gordon, Christopher T., Xue, Shifeng, Yigit, Goekhan, Filali, Hicham, Chen, Kelan, Rosins, Nadine, Yoshiura, Koh-ichiro, Oufadem, Myriam, Beck, Tamara J., McGowan, Ruth, Magee, Alex C., Altmueller, Janine, Dion, Camille, Thiele, Holger, Gurzau, Alexandra D., Nuernberg, Peter, Meschede, Dieter, Muehlbauer, Wolfgang, Okamoto, Nobuhiko, and Varghese, Vinod
- Subjects
food and beverages - Abstract
Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.
- Published
- 2017
4. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function
- Author
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Gurzau, Alexandra D., primary, Chen, Kelan, additional, Xue, Shifeng, additional, Dai, Weiwen, additional, Lucet, Isabelle S., additional, Ly, Thanh Thao Nguyen, additional, Reversade, Bruno, additional, Blewitt, Marnie E., additional, and Murphy, James M., additional
- Published
- 2018
- Full Text
- View/download PDF
5. SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite.
- Author
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Dion, Camille, Roche, Stéphane, Laberthonnière, Camille, Broucqsault, Natacha, Mariot, Virginie, Xue, Shifeng, Gurzau, Alexandra D, Nowak, Agnieszka, Gordon, Christopher T, Gaillard, Marie-Cécile, El-Yazidi, Claire, Thomas, Morgane, Schlupp-Robaglia, Andrée, Missirian, Chantal, Malan, Valérie, Ratbi, Liham, Sefiani, Abdelaziz, Wollnik, Bernd, Binetruy, Bernard, and Salort Campana, Emmanuelle
- Published
- 2019
- Full Text
- View/download PDF
6. SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite
- Author
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Reversade, Bruno, Dion, Camille, Roche, Stephane, Laberthonniere, Camille, Broucqsault, Natacha, Mariot, Virginie, Xue, Shifeng, Gurzau, Alexandra D., Nowak, Agnieszka, Gordon, Christopher T., Gaillard, Marie-Cecile, El-Yazidi, Claire, Thomas, Morgane, Schlupp-Robaglia, Andree, Missirian, Chantal, Malan, Valerie, Ratbi, Liham, Sefiani, Abdelaziz, Wollnik, Bernd, Binetruy, Bernard, Campana, Emmanuelle Salort, Attarian, Shahram, Bernard, Rafaelle, Nguyen, Karine, Amie, Jeanne, Dumonceaux, Julie, Murphy, James M., Dejardin, Jerome, Blewitt, Marnie E., Robin, Jerome D., Magdinier, Frederique, School of Medicine, and Department of Medical Genetics
- Subjects
Medicine ,Biochemistry and molecular biology ,Facioscapulohumeral muscular-dystrophy ,Pluripotent stem-cells ,Inactıve X-chromosome ,Gene ,Family ,Hypomethylation ,Mutations ,Chromatin ,Arhinia ,Adopts - Abstract
The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation., Association Francaise contre les Myopathies (AFM); Agence Nationale de la Recherche; Fondation Aix-Marseille Universite, Sante, Sport et developpement Durable; French Ministry of Education and FSH Society; Australian Government; Bellberry-Viertel Senior Medical Research Fellowship; Australian National Health and Medical Research Council (NHMRC) Fellowship; NHMRC grant; Independent Research Institute Infrastructure Scheme (IRIISS) support; Victorian State Government Operational Infrastructure Support; Aix Marseille University
- Published
- 2019
7. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function
- Author
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Isabelle S Lucet, Thanh Thao Nguyen Ly, James M. Murphy, Marnie E. Blewitt, Kelan Chen, Alexandra D. Gurzau, Weiwen Dai, Shifeng Xue, Bruno Reversade, ARD - Amsterdam Reproduction and Development, ACS - Diabetes & metabolism, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, Reversade, Bruno, Gurzau, Alexandra D., Chen, Kelan, Xue, Shifeng, Dai, Weiwen, Lucet, Isabelle S., Thanh Thao Nguyen Ly, Blewitt, Marnie E., Murphy, James M., School of Medicine, Department of Histology and Embryology, and Obstetrics and gynaecology
- Subjects
0301 basic medicine ,Eye Diseases ,Chromosomal Proteins, Non-Histone ,Protein Conformation ,ATPase ,Xenopus ,Mutation, Missense ,Sequence Homology ,Nose ,medicine.disease_cause ,Crystallography, X-Ray ,Biochemistry ,Choanal Atresia ,03 medical and health sciences ,Mice ,Xenopus laevis ,0302 clinical medicine ,Adenosine Triphosphate ,Protein Domains ,medicine ,Facioscapulohumeral muscular dystrophy ,Missense mutation ,Animals ,Humans ,Microphthalmos ,Epigenetics ,Amino Acid Sequence ,Muscular dystrophy ,Molecular Biology ,Loss function ,Adenosine Triphosphatases ,Mutation ,biology ,food and beverages ,Cell Biology ,biology.organism_classification ,medicine.disease ,Muscular Dystrophy, Facioscapulohumeral ,Cell biology ,030104 developmental biology ,Small-angle X-ray scattering (SAXS) ,Craniofacial development ,SMC ,Hinge domain ,biology.protein ,Enzymology ,Biochemistry and molecular biology ,030217 neurology & neurosurgery - Abstract
Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1) plays important roles in epigenetic silencing and normal mammalian development. Recently, heterozygous mutations in SMCHD1 have been reported in two disparate disorders: facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS). FSHD2-associated mutations lead to loss of function; however, whether BAMS is associated with loss- or gain-of-function mutations in SMCHD1 is unclear. Here, we have assessed the effect of SMCHD1 missense mutations from FSHD2 and BAMS patients on ATP hydrolysis activity and protein conformation and the effect of BAMS mutations on craniofacial development in a Xenopus model. These data demonstrated that FSHD2 mutations only result in decreased ATP hydrolysis, whereas many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus. Interestingly, a mutation reported in both an FSHD2 patient and a BAMS patient results in increased ATPase activity and a smaller Xenopus eye size. Mutations in the extended ATPase domain increased catalytic activity, suggesting critical regulatory intramolecular interactions and the possibility of targeting this region therapeutically to boost SMCHD1's activity to counter FSHD., Australian National Health and Medical Research Council Fellowship; Australian National Health and Medical Research Council IRIISS Grant; Australian Research Training Program scholarship; Cancer Council Victoria fellowship; Bellberry-Viertel Senior Medical Research Fellowship; A*STAR BMRC YIG; NMRC YIRG; Victorian State Government Operational Infrastructure Support; Australian Cancer Research Foundation
- Published
- 2018
8. MORC2 phosphorylation fine tunes its DNA compaction activity.
- Author
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Tan W, Park JV, Venugopal H, Lou JQ, Dias PS, Baldoni PL, Dite T, Moon KW, Keenan CR, Gurzau AD, Leis A, Yousef J, Vaibhav V, Dagley LF, Ang CS, Corso L, Davidovich C, Vervoort SJ, Smyth GK, Blewitt ME, Allan RS, Hinde E, D'Arcy S, Ryu JK, and Shakeel S
- Abstract
Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.
- Published
- 2024
- Full Text
- View/download PDF
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