Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy
Virginie Mariot PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorStephane Roche PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorChristophe Hourdé PhD
Physiology and Exercise Laboratory, EA4338, Technolac Scientific Campus, University of Savoie Mont Blanc, Le Bourget-du-Lac
Search for more papers by this authorDebora Portilho PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorSabrina Sacconi MD, PhD
Mixed Unit of Research 7277, National Center for Scientific Research, Nice University Hospital, Nice
Neuromuscular Disease Reference Center, Nice University Hospital, Nice
Search for more papers by this authorFrancesca Puppo PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorStephanie Duguez PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorPhilippe Rameau
Imaging and Cytometry Platform, Gustave Roussy Institute, Villejuif
Search for more papers by this authorNathalie Caruso PhD
Aix-Marseille University, Developmental Biology Institute of Marseille, National Center for Scientific Research Mixed Unit of Research 7288, Luminy Scientific Park, Marseille
Search for more papers by this authorAnne-Lise Delezoide MD
Department of Developmental Biology, Robert Debré Hospital, U696, National Institute of Health and Medical Research, Paris
Search for more papers by this authorClaude Desnuelle MD
Mixed Unit of Research 7277, National Center for Scientific Research, Nice University Hospital, Nice
Neuromuscular Disease Reference Center, Nice University Hospital, Nice
Search for more papers by this authorBettina Bessières MD
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
Search for more papers by this authorSophie Collardeau MD
East Pathology Center, University Hospital Center, Lyon, Bron
Search for more papers by this authorLeonard Feasson MD
Physiology and Exercise Laboratory EA4338, Rare Neuromuscular Diseases Referent Center, Rhône-Alpes Bellevue Hospital, University Hospital Center of Saint-Étienne, Saint-Étienne
Search for more papers by this authorThierry Maisonobe MD
Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorFrederique Magdinier PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorFrançoise Helmbacher PhD
Aix-Marseille University, Developmental Biology Institute of Marseille, National Center for Scientific Research Mixed Unit of Research 7288, Luminy Scientific Park, Marseille
Search for more papers by this authorGillian Butler-Browne PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorVincent Mouly PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorCorresponding Author
Julie Dumonceaux PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Address correspondence to Dr Dumonceaux, Center of Research in Myology/Institut de Myologie UMR974 — UPMC Université Paris 6/Inserm/FRE3617 — CNRS, 47, boulevard de l'hôpital, G.H. Pitié Salpétrière-Batiment Babinski, Paris Cedex 13, France. E-mail address: [email protected]Search for more papers by this authorVirginie Mariot PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorStephane Roche PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorChristophe Hourdé PhD
Physiology and Exercise Laboratory, EA4338, Technolac Scientific Campus, University of Savoie Mont Blanc, Le Bourget-du-Lac
Search for more papers by this authorDebora Portilho PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorSabrina Sacconi MD, PhD
Mixed Unit of Research 7277, National Center for Scientific Research, Nice University Hospital, Nice
Neuromuscular Disease Reference Center, Nice University Hospital, Nice
Search for more papers by this authorFrancesca Puppo PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorStephanie Duguez PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorPhilippe Rameau
Imaging and Cytometry Platform, Gustave Roussy Institute, Villejuif
Search for more papers by this authorNathalie Caruso PhD
Aix-Marseille University, Developmental Biology Institute of Marseille, National Center for Scientific Research Mixed Unit of Research 7288, Luminy Scientific Park, Marseille
Search for more papers by this authorAnne-Lise Delezoide MD
Department of Developmental Biology, Robert Debré Hospital, U696, National Institute of Health and Medical Research, Paris
Search for more papers by this authorClaude Desnuelle MD
Mixed Unit of Research 7277, National Center for Scientific Research, Nice University Hospital, Nice
Neuromuscular Disease Reference Center, Nice University Hospital, Nice
Search for more papers by this authorBettina Bessières MD
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
Search for more papers by this authorSophie Collardeau MD
East Pathology Center, University Hospital Center, Lyon, Bron
Search for more papers by this authorLeonard Feasson MD
Physiology and Exercise Laboratory EA4338, Rare Neuromuscular Diseases Referent Center, Rhône-Alpes Bellevue Hospital, University Hospital Center of Saint-Étienne, Saint-Étienne
Search for more papers by this authorThierry Maisonobe MD
Department of Clinical Neurophysiology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorFrederique Magdinier PhD
Timone Faculty of Medicine, Aix-Marseille University, Mixed health research unit 910, National Institute of Health and Medical Research, Marseille
Search for more papers by this authorFrançoise Helmbacher PhD
Aix-Marseille University, Developmental Biology Institute of Marseille, National Center for Scientific Research Mixed Unit of Research 7288, Luminy Scientific Park, Marseille
Search for more papers by this authorGillian Butler-Browne PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorVincent Mouly PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Search for more papers by this authorCorresponding Author
Julie Dumonceaux PhD
Center of Research in Myology, Pierre and Marie Curie University, Sorbonne Universities, Paris
Mixed health research unit 974, National Institute of Health and Medical Research, Paris
Unit undergoing review 3617, National Center for Scientific Research, Paris
Institute of Myology, Paris
Address correspondence to Dr Dumonceaux, Center of Research in Myology/Institut de Myologie UMR974 — UPMC Université Paris 6/Inserm/FRE3617 — CNRS, 47, boulevard de l'hôpital, G.H. Pitié Salpétrière-Batiment Babinski, Paris Cedex 13, France. E-mail address: [email protected]Search for more papers by this authorAbstract
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. Ann Neurol 2015;78:387–400
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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| ana24446-sup-0001-supptable1.pdf65.1 KB |
Supplementary Information Table 1. |
| ana24446-sup-0002-supptable2.pdf91.3 KB |
Supplementary Information Table 2. |
| ana24446-sup-0003-supptable3.pdf49.8 KB |
Supplementary Information Table 3. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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