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...
Saved in:
Published in | Human molecular genetics Vol. 21; no. 20; pp. 4419 - 4430 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Oxford University Press
15.10.2012
|
Subjects | |
Online Access | Get full text |
ISSN | 1460-2083 0964-6906 1460-2083 |
DOI | 10.1093/hmg/dds284 |
Cover
Abstract | 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. |
---|---|
AbstractList | 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. 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.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. 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. |
Author | Chen, Jennifer C J King, Oliver D Kunkel, Louis M Homma, Sachiko Beermann, Mary Lou Rahimov, Fedik Emerson, Jr, Charles P Arashiro, Patricia Miller, Jeffrey B Jones, Takako Iida Wagner, Kathryn R Jones, Peter L |
AuthorAffiliation | 2 The Eunice Kennedy Shriver National Institute of Child Health, Human Development Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center for Facioscapulohumeral Muscular Dystrophy 5 Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, and the Departments of Neurology and Neuroscience , The Johns Hopkins School of Medicine , Baltimore, MD , USA 1 Boston Biomedical Research Institute , 64 Grove St, Watertown, MA 02472 , USA 4 The Manton Center for Orphan Disease Research , Children's Hospital , Boston, MA USA and 3 Program in Genomics, Division of Genetics , Children's Hospital Boston, Harvard Medical School , Boston, MA USA |
AuthorAffiliation_xml | – name: 3 Program in Genomics, Division of Genetics , Children's Hospital Boston, Harvard Medical School , Boston, MA USA – name: 4 The Manton Center for Orphan Disease Research , Children's Hospital , Boston, MA USA and – name: 5 Center for Genetic Muscle Disorders, The Kennedy Krieger Institute, and the Departments of Neurology and Neuroscience , The Johns Hopkins School of Medicine , Baltimore, MD , USA – name: 2 The Eunice Kennedy Shriver National Institute of Child Health, Human Development Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center for Facioscapulohumeral Muscular Dystrophy – name: 1 Boston Biomedical Research Institute , 64 Grove St, Watertown, MA 02472 , USA |
Author_xml | – sequence: 1 givenname: Takako Iida surname: Jones fullname: Jones, Takako Iida organization: Boston Biomedical Research Institute, Watertown, MA 02472, USA – sequence: 2 givenname: Jennifer C J surname: Chen fullname: Chen, Jennifer C J – sequence: 3 givenname: Fedik surname: Rahimov fullname: Rahimov, Fedik – sequence: 4 givenname: Sachiko surname: Homma fullname: Homma, Sachiko – sequence: 5 givenname: Patricia surname: Arashiro fullname: Arashiro, Patricia – sequence: 6 givenname: Mary Lou surname: Beermann fullname: Beermann, Mary Lou – sequence: 7 givenname: Oliver D surname: King fullname: King, Oliver D – sequence: 8 givenname: Jeffrey B surname: Miller fullname: Miller, Jeffrey B – sequence: 9 givenname: Louis M surname: Kunkel fullname: Kunkel, Louis M – sequence: 10 givenname: Charles P surname: Emerson, Jr fullname: Emerson, Jr, Charles P – sequence: 11 givenname: Kathryn R surname: Wagner fullname: Wagner, Kathryn R – sequence: 12 givenname: Peter L surname: Jones fullname: Jones, Peter L |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/22798623$$D View this record in MEDLINE/PubMed |
BookMark | eNqFkc1u1TAQhS1URH9gwwMgL9nc1n9xEhZIqLSAVIlNK7GLJvHkxiix04x9xX2MvnHTUlBZsZqRzsw352iO2UGIARl7K8WpFLU-G6btmXOkKvOCHUljxUaJSh886w_ZMdFPIaQ1unzFDpUq68oqfcTuLqHzkTqY8xiHPOECI58ydXmEhbs9pSXOw573MPlxzyll55F47Pnnmx-G4695QSIfwweOO-8wdMj7uG56QiDkU3S-97gQh-A48NsMIfkEye8eRRwfWDOkIW4xIHl6zV72MBK-eaon7Oby4vr86-bq-5dv55-uNrNSddrYtnCyrqSpykKbwoFtWyjbuiuqulRqbW1RlEaYGoztBZS2ExKM0mCF1EroE_bxN3fO7YSuw5DW7M28-AmWfRPBN_8qwQ_NNu6a9VptbLEC3j8BlnibkVIzeepwHCFgzNRIo41QdnX7_1GxBtGFEQ_Ud89t_fXz52X6HmpZnWs |
ContentType | Journal Article |
Copyright | The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2012 |
Copyright_xml | – notice: The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2012 |
DBID | CGR CUY CVF ECM EIF NPM 7X8 8FD FR3 P64 RC3 5PM |
DOI | 10.1093/hmg/dds284 |
DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic Technology Research Database Engineering Research Database Biotechnology and BioEngineering Abstracts Genetics Abstracts PubMed Central (Full Participant titles) |
DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic Genetics Abstracts Engineering Research Database Technology Research Database Biotechnology and BioEngineering Abstracts |
DatabaseTitleList | MEDLINE - Academic Genetics Abstracts MEDLINE |
Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Medicine Biology |
EISSN | 1460-2083 |
EndPage | 4430 |
ExternalDocumentID | PMC3459465 22798623 |
Genre | Research Support, Non-U.S. Gov't Journal Article Research Support, N.I.H., Extramural |
GrantInformation_xml | – fundername: NIAMS NIH HHS grantid: AR060328 – fundername: NICHD NIH HHS grantid: U54 HD060848 – fundername: NHLBI NIH HHS grantid: R01 HL064641 – fundername: NHLBI NIH HHS grantid: HL064641 – fundername: NICHD NIH HHS grantid: 5U54HD060848 – fundername: NIAMS NIH HHS grantid: R01 AR060328 – fundername: NIAMS NIH HHS grantid: R01 AR055877 |
GroupedDBID | --- -DZ -E4 .2P .I3 .XZ .ZR 0R~ 18M 1TH 29I 2WC 4.4 482 48X 53G 5GY 5RE 5VS 5WA 5WD 70D AABZA AACZT AAIMJ AAJKP AAJQQ AAMDB AAMVS AAOGV AAPNW AAPQZ AAPXW AARHZ AAUAY AAUQX AAVAP AAVLN ABDFA ABEJV ABEUO ABGNP ABIXL ABJNI ABKDP ABLJU ABMNT ABNHQ ABNKS ABPQP ABPTD ABQLI ABVGC ABWST ABXVV ABXZS ABZBJ ACGFO ACGFS ACPRK ACUFI ACUTJ ACUTO ADBBV ADEYI ADEZT ADFTL ADGKP ADGZP ADHKW ADHZD ADIPN ADNBA ADOCK ADQBN ADRTK ADVEK ADYVW ADZTZ ADZXQ AEGPL AEGXH AEJOX AEKSI AELWJ AEMDU AENEX AENZO AEPUE AETBJ AEWNT AFFZL AFGWE AFIYH AFOFC AFYAG AGINJ AGKEF AGORE AGQXC AGSYK AHMBA AHMMS AHXPO AIAGR AIJHB AJBYB AJEEA AJNCP AKHUL AKWXX ALMA_UNASSIGNED_HOLDINGS ALUQC ALXQX APIBT APWMN ARIXL ATGXG AXUDD AYOIW BAWUL BAYMD BCRHZ BEYMZ BHONS BQDIO BSWAC BTRTY BVRKM C45 CDBKE CGR COF CS3 CUY CVF CZ4 DAKXR DIK DILTD DU5 D~K EBS ECM EE~ EIF EJD EMOBN F5P F9B FHSFR FLUFQ FOEOM FOTVD FQBLK GAUVT GJXCC GX1 H13 H5~ HAR HW0 HZ~ IH2 IOX J21 JXSIZ KAQDR KBUDW KOP KQ8 KSI KSN L7B M-Z ML0 N9A NGC NLBLG NOMLY NOYVH NPM NU- NVLIB O0~ O9- OAWHX OBC OBOKY OBS OCZFY ODMLO OEB OJQWA OJZSN OK1 OPAEJ OVD OWPYF P2P PAFKI PEELM PQQKQ Q1. Q5Y R44 RD5 ROL ROX ROZ RUSNO RW1 RXO SJN TEORI TJX TLC TMA TR2 W8F WOQ X7H XSW YAYTL YKOAZ YXANX ZKX ~91 7X8 8FD FR3 P64 RC3 5PM |
ID | FETCH-LOGICAL-p229t-6b5d19814875345da6bba7b9c589722a7b65574049a46f0a76c01a423a6013203 |
ISSN | 1460-2083 0964-6906 |
IngestDate | Thu Aug 21 13:59:46 EDT 2025 Thu Jul 10 19:01:31 EDT 2025 Sat Sep 27 21:58:21 EDT 2025 Mon Jul 21 06:03:50 EDT 2025 |
IsDoiOpenAccess | false |
IsOpenAccess | true |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 20 |
Language | English |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-p229t-6b5d19814875345da6bba7b9c589722a7b65574049a46f0a76c01a423a6013203 |
Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. |
PMID | 22798623 |
PQID | 1081435405 |
PQPubID | 23479 |
PageCount | 12 |
ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_3459465 proquest_miscellaneous_1434026229 proquest_miscellaneous_1081435405 pubmed_primary_22798623 |
PublicationCentury | 2000 |
PublicationDate | 2012-10-15 |
PublicationDateYYYYMMDD | 2012-10-15 |
PublicationDate_xml | – month: 10 year: 2012 text: 2012-10-15 day: 15 |
PublicationDecade | 2010 |
PublicationPlace | England |
PublicationPlace_xml | – name: England |
PublicationTitle | Human molecular genetics |
PublicationTitleAlternate | Hum Mol Genet |
PublicationYear | 2012 |
Publisher | Oxford University Press |
Publisher_xml | – name: Oxford University Press |
SSID | ssj0016437 |
Score | 2.453672 |
Snippet | Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions... |
SourceID | pubmedcentral proquest pubmed |
SourceType | Open Access Repository Aggregation Database Index Database |
StartPage | 4419 |
SubjectTerms | Adult Aged Cohort Studies Disease Progression Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Immunohistochemistry Middle Aged Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Muscular Dystrophy, Facioscapulohumeral - genetics Muscular Dystrophy, Facioscapulohumeral - metabolism Muscular Dystrophy, Facioscapulohumeral - pathology RNA, Messenger - metabolism |
Title | Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis |
URI | https://www.ncbi.nlm.nih.gov/pubmed/22798623 https://www.proquest.com/docview/1081435405 https://www.proquest.com/docview/1434026229 https://pubmed.ncbi.nlm.nih.gov/PMC3459465 |
Volume | 21 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3bbtNAEF2FIhAvCMot5aJF4i0ytZ312uYNtY1SaIuEEilv0fpWW8FxVMeVyl_wFfwmM3txHIhQ4cWynNXG9hzPzuycmSHkXebFcWonyO4PPYvxDL65YRpYqXCwfFbk-x4mCp9f8PGUfZp5s17vZ4e11Kyj9_H3nXkl_yNVuAZyxSzZf5BsOylcgHOQLxxBwnC8lYxHIi6qOhar5luVN3J7aVA2mlqa3NTrqwreotnEqBVlEM3D4-mMYXF_RYKV5I5UtxeVvEMdtsE-OUWGzbJVTVdMwVzKrDTkG8kmOpIxDVZkdYlKs6i7xq4KEJSmAS92a8aUyQ1p0fQJmIiFWFSD02KzPXBkskY0-2bQCWB9FTkg7Fra3bD2trlG46oshdrmjvNiUXV3NBwXlwKV02m2JjmzsICyWqOUYmbcBtmrpjdGc6vcao1Q1-7oYTDyws6azpgK_vyxXqhaWnkJanWUJLWr2tVtl-W--DIfTc_O5pOT2eQOuev6nGOrjOPTz224CqOfsqijvnFTBzccHsLch2rmXT7M71Tcjm0zeUQeaqeEflQIe0x66XKf3FNtSm_2yf1zTcB4Qn7sgBw1kKMt5KiCHNWQo1VGEXJ0A7kP1ACOAuCoBhxtAUcBcFTQLuCoBBzO1QXcUzIdnUyOxpbu6mGtXDdcWzzyEicMHOkpMy8RPIqEH4WxF4S-68Ip9zyfgecqQHXYwuex7Qiw-gXHuKA9fEb2loDPF4RGQQbmeCKGdpSxFHwZcEdiGCiCgIUpD_rkrXnjc9CaGAoTy7RqaiyLi44CeCt_GcOGzHY53HSfPFdSmq9UCZg51t0MwHPoE39Lfu0ArNq-_cuyyGX1dnjmkHHv4Bb_-5I82Hwfr8je-qpJX4MNvI7eSPz9AkYzvPk |
linkProvider | Flying Publisher |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Facioscapulohumeral+muscular+dystrophy+family+studies+of+DUX4+expression%3A+evidence+for+disease+modifiers+and+a+quantitative+model+of+pathogenesis&rft.jtitle=Human+molecular+genetics&rft.au=Jones%2C+Takako+Iida&rft.au=Chen%2C+Jennifer+C+J&rft.au=Rahimov%2C+Fedik&rft.au=Homma%2C+Sachiko&rft.date=2012-10-15&rft.issn=0964-6906&rft.eissn=1460-2083&rft.volume=21&rft.issue=20&rft.spage=4419&rft.epage=4430&rft_id=info:doi/10.1093%2Fhmg%2Fdds284&rft.externalDBID=NO_FULL_TEXT |
thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1460-2083&client=summon |
thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1460-2083&client=summon |
thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1460-2083&client=summon |