Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy
Virginie Mariot
(1)
,
S. Roche
(2)
,
Débora Portilho
(1)
,
Sabrina Sacconi
(3)
,
Francesca Puppo
(2)
,
Stéphanie Duguez
(1)
,
Philippe Rameau
(4)
,
Nathalie Caruso
(5)
,
A.L Delezoide
(6)
,
Claude Desnuelle
(3)
,
Bettina Bessières
(7)
,
Sophie Collardeau
(8)
,
Léonard Feasson
(9)
,
Thierry Maisonobe
(10)
,
Frédérique Magdinier
(2)
,
Françoise Helmbacher
(5)
,
Gillian Butler-Browne
(1)
,
Vincent Mouly
(1)
,
Julie Dumonceaux
(1)
,
Christophe Hourdé
(9)
1
Centre de recherche en myologie
2 GMGF - Génétique Médicale et Génomique Fonctionnelle
3 IBV - Institut de Biologie Valrose
4 PFIC - Plateforme imagerie et cytométrie
5 IBDM - Institut de Biologie du Développement de Marseille
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
8 CHU Lyon
9 LIBM - Laboratoire Interuniversitaire de Biologie de la Motricité
10 CHU Pitié-Salpêtrière [AP-HP]
2 GMGF - Génétique Médicale et Génomique Fonctionnelle
3 IBV - Institut de Biologie Valrose
4 PFIC - Plateforme imagerie et cytométrie
5 IBDM - Institut de Biologie du Développement de Marseille
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
8 CHU Lyon
9 LIBM - Laboratoire Interuniversitaire de Biologie de la Motricité
10 CHU Pitié-Salpêtrière [AP-HP]
S. Roche
- Fonction : Auteur
- PersonId : 15416
- IdHAL : stephane-roche
- ORCID : 0000-0001-6660-1317
- IdRef : 189678313
Francesca Puppo
- Fonction : Auteur
- PersonId : 171577
- IdHAL : francesca-puppo
- ORCID : 0000-0002-9823-0810
Léonard Feasson
- Fonction : Auteur
- PersonId : 1063699
- ORCID : 0000-0002-8163-5539
Frédérique Magdinier
- Fonction : Auteur
- PersonId : 16264
- IdHAL : frederique-magdinier
- ORCID : 0000-0002-0159-9559
- IdRef : 157603660
Françoise Helmbacher
- Fonction : Auteur
- PersonId : 19949
- IdHAL : francoise-helmbacher
- ORCID : 0000-0001-6822-1246
- IdRef : 158868862
Gillian Butler-Browne
- Fonction : Auteur
- PersonId : 915891
- IdHAL : gillian-butler-browne
Vincent Mouly
- Fonction : Auteur
- PersonId : 915892
- IdHAL : vincentmoulyupmcfr
- ORCID : 0000-0003-3809-4033
Christophe Hourdé
- Fonction : Auteur
- PersonId : 878834
Résumé
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.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy
|
Résumé |
en
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.
|
Auteur(s) |
Virginie Mariot
1
, S. Roche
2
, Débora Portilho
1
, Sabrina Sacconi
3
, Francesca Puppo
2
, Stéphanie Duguez
1
, Philippe Rameau
4
, Nathalie Caruso
5
, A.L Delezoide
6
, Claude Desnuelle
3
, Bettina Bessières
7
, Sophie Collardeau
8
, Léonard Feasson
9
, Thierry Maisonobe
10
, Frédérique Magdinier
2
, Françoise Helmbacher
5
, Gillian Butler-Browne
1
, Vincent Mouly
1
, Julie Dumonceaux
1
, Christophe Hourdé
9
1
Centre de recherche en myologie
( 247291 )
- Bâtiment Babinski 47/83 Bd de L'Hôpital 75013 Paris
- France
2
GMGF -
Génétique Médicale et Génomique Fonctionnelle
( 46221 )
- Faculté de Médecine - 27 boulevard Jean Moulin 13385 Marseille Cedex 05
- France
3
IBV -
Institut de Biologie Valrose
( 182201 )
- Faculté des Sciences, parc Valrose 06108 Nice cedex 2
- France
4
PFIC -
Plateforme imagerie et cytométrie
( 457279 )
- France
5
IBDM -
Institut de Biologie du Développement de Marseille
( 1060434 )
- Case 907 - Parc Scientifique de Luminy 13288 Marseille Cedex 9
- France
6
AP-HP Hôpital universitaire Robert-Debré [Paris]
( 426105 )
- 48, boulevard Sérurier – 75019 Paris
- France
7
Inserm U781 -
Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
( 2827 )
- Gh Necker - Enfants Malades 149, Rue de Sevres 75743 PARIS CEDEX 15
- France
8
CHU Lyon
( 339246 )
-
- France
9
LIBM -
Laboratoire Interuniversitaire de Biologie de la Motricité
( 93721 )
- Faculté de Médecin Campus Santé Innovations - Bâtiment IRMIS - 10 rue de la Marandière 42270 Saint Priest en Jarez
Université Savoie Mont Blanc - Campus Scientifique - 73370 Le Bourget du Lac
UFR STAPS - Université Claude Bernard Lyon I - 27/29 Boulevard du 11 novembre 1918 - 69622 Villeurbanne Cedex
- France
10
CHU Pitié-Salpêtrière [AP-HP]
( 353778 )
- 47-83 Boulevard de l'Hôpital, 75013 Paris
- France
|
Numéro |
3
|
Date de publication électronique |
2015-07-03
|
Nom de la revue |
|
Date de publication |
2015
|
Audience |
Internationale
|
Page/Identifiant |
387-400
|
Volume |
78
|
Langue du document |
Anglais
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Domaine(s) |
|
Mots-clés |
en
Facio-Scapulo-Humeral Dystrophy, DUX4, DNA methylation, Haploinsufficiency, FSHD, SMCHD1, DNA combing, FAT1-protocadherin
|
DOI | 10.1002/ana.24446 |
Origine :
Fichiers produits par l'(les) auteur(s)
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