Facioscapulohumeral muscular dystrophy family studies of DUX4 expression : evidence for disease modifiers and a quantitative model of pathogenesis
Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2012 |
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| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Human molecular genetics - 21(2012), 20 vom: 15. Okt., Seite 4419-30 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jones, Takako Iida [VerfasserIn] |
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| Themen: |
DUX4L1 protein, human |
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| Anmerkungen: |
Date Completed 21.06.2013 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM219445974 |
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| 100 | 1 | |a Jones, Takako Iida |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Facioscapulohumeral muscular dystrophy family studies of DUX4 expression |b evidence for disease modifiers and a quantitative model of pathogenesis |
| 264 | 1 | |c 2012 | |
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| 500 | |a Date Completed 21.06.2013 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a DUX4L1 protein, human |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
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| 700 | 1 | |a Chen, Jennifer C J |e verfasserin |4 aut | |
| 700 | 1 | |a Rahimov, Fedik |e verfasserin |4 aut | |
| 700 | 1 | |a Homma, Sachiko |e verfasserin |4 aut | |
| 700 | 1 | |a Arashiro, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Beermann, Mary Lou |e verfasserin |4 aut | |
| 700 | 1 | |a King, Oliver D |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Jeffrey B |e verfasserin |4 aut | |
| 700 | 1 | |a Kunkel, Louis M |e verfasserin |4 aut | |
| 700 | 1 | |a Emerson, Charles P |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Wagner, Kathryn R |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Peter L |e verfasserin |4 aut | |
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