Virginie Mariot1,2,3,4, Stephane Roche5, Christophe Hourdé6, Debora Portilho1,2,3,4, Sabrina Sacconi7,8, Francesca Puppo5, Stephanie Duguez1,2,3,4, Philippe Rameau9, Nathalie Caruso10, Anne-Lise Delezoide11, Claude Desnuelle7,8, Bettina Bessières12, Sophie Collardeau13, Leonard Feasson14, Thierry Maisonobe15, Frederique Magdinier5, Françoise Helmbacher10, Gillian Butler-Browne1,2,3,4, Vincent Mouly1,2,3,4, Julie Dumonceaux1,2,3,4. 1. Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris. 2. Mixed health research unit 974, National Institute of Health and Medical Research, Paris. 3. Unit undergoing review 3617, National Center for Scientific Research, Paris. 4. Institute of Myology, Paris. 5. Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille. 6. Physiology and Exercise Laboratory, EA4338, Technolac Scientific Campus, University of Savoie Mont Blanc, Le Bourget-du-Lac. 7. Mixed Unit of Research 7277, National Center for Scientific Research, Nice University Hospital, Nice. 8. Neuromuscular Disease Reference Center, Nice University Hospital, Nice. 9. Imaging and Cytometry Platform, Gustave Roussy Institute, Villejuif. 10. Aix-Marseille University, Developmental Biology Institute of Marseille, National Center for Scientific Research Mixed Unit of Research 7288, Luminy Scientific Park, Marseille. 11. Department of Developmental Biology, Robert Debré Hospital, U696, National Institute of Health and Medical Research, Paris. 12. U781, National Institute of Health and Medical Research and IMAGINE Foundation, Department of Genetics, Necker Hospital for Sick Children, Public Hospital Network of Paris and Paris Descartes University, Paris. 13. East Pathology Center, University Hospital Center, Lyon, Bron. 14. Physiology and Exercise Laboratory EA4338, Rare Neuromuscular Diseases Referent Center, Rhône-Alpes Bellevue Hospital, University Hospital Center of Saint-Étienne, Saint-Étienne. 15. Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital Group, Paris, France.
Abstract
OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. Because we have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes, we have investigated the expression of the human FAT1 gene in FSHD. METHODS: We first analyzed FAT1 expression in FSHD adult muscles and determined whether FAT1 expression was driven by DUX4. We next determined FAT1 expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of Fat1 expression in developing mouse embryos. RESULTS: We demonstrated that FAT1 expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles that are affected at early stages of FSHD progression than in muscles that are affected later or are nonaffected; and (2) in adult muscle biopsies, FAT1 expression is lower in FSHD muscles compared to control muscles. INTERPRETATION: We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype.
OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. Because we have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes, we have investigated the expression of the humanFAT1 gene in FSHD. METHODS: We first analyzed FAT1 expression in FSHD adult muscles and determined whether FAT1 expression was driven by DUX4. We next determined FAT1 expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of Fat1 expression in developing mouse embryos. RESULTS: We demonstrated that FAT1 expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles that are affected at early stages of FSHD progression than in muscles that are affected later or are nonaffected; and (2) in adult muscle biopsies, FAT1 expression is lower in FSHD muscles compared to control muscles. INTERPRETATION: We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype.
Authors: Davut Pehlivan; Yavuz Bayram; Nilay Gunes; Zeynep Coban Akdemir; Anju Shukla; Tatjana Bierhals; Burcu Tabakci; Yavuz Sahin; Alper Gezdirici; Jawid M Fatih; Elif Yilmaz Gulec; Gozde Yesil; Jaya Punetha; Zeynep Ocak; Christopher M Grochowski; Ender Karaca; Hatice Mutlu Albayrak; Periyasamy Radhakrishnan; Haktan Bagis Erdem; Ibrahim Sahin; Timur Yildirim; Ilhan A Bayhan; Aysegul Bursali; Muhsin Elmas; Zafer Yuksel; Ozturk Ozdemir; Fatma Silan; Onur Yildiz; Osman Yesilbas; Sedat Isikay; Burhan Balta; Shen Gu; Shalini N Jhangiani; Harsha Doddapaneni; Jianhong Hu; Donna M Muzny; Eric Boerwinkle; Richard A Gibbs; Konstantinos Tsiakas; Maja Hempel; Katta Mohan Girisha; Davut Gul; Jennifer E Posey; Nursel H Elcioglu; Beyhan Tuysuz; James R Lupski Journal: Am J Hum Genet Date: 2019-06-20 Impact factor: 11.025
Authors: Richard J L F Lemmers; Patrick J van der Vliet; Ana Blatnik; Judit Balog; Janez Zidar; Don Henderson; Rianne Goselink; Stephen J Tapscott; Nicol C Voermans; Rabi Tawil; George W A M Padberg; Baziel Gm van Engelen; Silvère M van der Maarel Journal: J Med Genet Date: 2021-01-12 Impact factor: 6.318
Authors: Jérôme D Robin; Andrew T Ludlow; Kimberly Batten; Marie-Cécile Gaillard; Guido Stadler; Frédérique Magdinier; Woodring E Wright; Jerry W Shay Journal: Genome Res Date: 2015-09-10 Impact factor: 9.043
Authors: Matthew Thorley; Stéphanie Duguez; Emilia Maria Cristina Mazza; Sara Valsoni; Anne Bigot; Kamel Mamchaoui; Brennan Harmon; Thomas Voit; Vincent Mouly; William Duddy Journal: Skelet Muscle Date: 2016-12-08 Impact factor: 4.912
Authors: Hyung Jun Park; Wookjae Lee; Se Hoon Kim; Jung Hwan Lee; Ha Young Shin; Seung Min Kim; Kee Duk Park; Ji Hyun Lee; Young Chul Choi Journal: Yonsei Med J Date: 2018-03 Impact factor: 2.759