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

Virginie Mariot, Stephane Roche, Christophe Hourdé, Debora Portilho, Sabrina Sacconi, Francesca Puppo, Stephanie Duguez, Philippe Rameau, Nathalie Caruso, Anne-Lise Delezoide, Claude Desnuelle, Bettina Bessières, Sophie Collardeau, Leonard Feasson, Thierry Maisonobe, Frederique Magdinier, Françoise Helmbacher, Gillian Butler-Browne, Vincent Mouly, Julie Dumonceaux

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    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.
    LanguageEnglish
    Pages387-400
    JournalAnnals of Neurology
    Volume78
    Issue number3
    Early online date3 Jul 2015
    DOIs
    Publication statusPublished - Sep 2015

    Fingerprint

    Facioscapulohumeral Muscular Dystrophy
    Muscles
    Phenotype
    Embryonic Structures
    Biopsy
    Chromosomes, Human, Pair 4
    Genes
    Fetus
    Transcription Factors
    Genotype

    Keywords

    • FSHD
    • FAT1

    Cite this

    Mariot, V., Roche, S., Hourdé, C., Portilho, D., Sacconi, S., Puppo, F., ... Dumonceaux, J. (2015). Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. Annals of Neurology, 78(3), 387-400. https://doi.org/10.1002/ana.24446
    Mariot, Virginie ; Roche, Stephane ; Hourdé, Christophe ; Portilho, Debora ; Sacconi, Sabrina ; Puppo, Francesca ; Duguez, Stephanie ; Rameau, Philippe ; Caruso, Nathalie ; Delezoide, Anne-Lise ; Desnuelle, Claude ; Bessières, Bettina ; Collardeau, Sophie ; Feasson, Leonard ; Maisonobe, Thierry ; Magdinier, Frederique ; Helmbacher, Françoise ; Butler-Browne, Gillian ; Mouly, Vincent ; Dumonceaux, Julie. / Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. In: Annals of Neurology. 2015 ; Vol. 78, No. 3. pp. 387-400.
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    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.",
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    author = "Virginie Mariot and Stephane Roche and Christophe Hourd{\'e} and Debora Portilho and Sabrina Sacconi and Francesca Puppo and Stephanie Duguez and Philippe Rameau and Nathalie Caruso and Anne-Lise Delezoide and Claude Desnuelle and Bettina Bessi{\`e}res and Sophie Collardeau and Leonard Feasson and Thierry Maisonobe and Frederique Magdinier and Fran{\cc}oise Helmbacher and Gillian Butler-Browne and Vincent Mouly and Julie Dumonceaux",
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    Mariot, V, Roche, S, Hourdé, C, Portilho, D, Sacconi, S, Puppo, F, Duguez, S, Rameau, P, Caruso, N, Delezoide, A-L, Desnuelle, C, Bessières, B, Collardeau, S, Feasson, L, Maisonobe, T, Magdinier, F, Helmbacher, F, Butler-Browne, G, Mouly, V & Dumonceaux, J 2015, 'Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy', Annals of Neurology, vol. 78, no. 3, pp. 387-400. https://doi.org/10.1002/ana.24446

    Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. / Mariot, Virginie; Roche, Stephane; Hourdé, Christophe; Portilho, Debora; Sacconi, Sabrina; Puppo, Francesca; Duguez, Stephanie; Rameau, Philippe; Caruso, Nathalie; Delezoide, Anne-Lise; Desnuelle, Claude; Bessières, Bettina; Collardeau, Sophie; Feasson, Leonard; Maisonobe, Thierry; Magdinier, Frederique; Helmbacher, Françoise; Butler-Browne, Gillian; Mouly, Vincent; Dumonceaux, Julie.

    In: Annals of Neurology, Vol. 78, No. 3, 09.2015, p. 387-400.

    Research output: Contribution to journalArticle

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    T1 - Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

    AU - Mariot, Virginie

    AU - Roche, Stephane

    AU - Hourdé, Christophe

    AU - Portilho, Debora

    AU - Sacconi, Sabrina

    AU - Puppo, Francesca

    AU - Duguez, Stephanie

    AU - Rameau, Philippe

    AU - Caruso, Nathalie

    AU - Delezoide, Anne-Lise

    AU - Desnuelle, Claude

    AU - Bessières, Bettina

    AU - Collardeau, Sophie

    AU - Feasson, Leonard

    AU - Maisonobe, Thierry

    AU - Magdinier, Frederique

    AU - Helmbacher, Françoise

    AU - Butler-Browne, Gillian

    AU - Mouly, Vincent

    AU - Dumonceaux, Julie

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    Y1 - 2015/9

    N2 - 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.

    AB - 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.

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    KW - FAT1

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    DO - 10.1002/ana.24446

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