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Ann Neurol. 2015 Sep;78(3):387-400. doi: 10.1002/ana.24446. Epub 2015 Jul 3.

Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy.

Author information

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.

PMID:
26018399
DOI:
10.1002/ana.24446
[Indexed for MEDLINE]

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