title: The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) patients carry contractions of the D4Z4-tandem repeat array on chromosome 4q35. Decrease in D4Z4 copy number is thought to alter a chromatin structure and activate expression of neighboring genes. D4Z4 contains a putative double-homeobox gene called DUX4. We identified DUX4 mRNAs in cells transfected with genomic fragments containing the DUX4 gene. Using RT-PCR we also recognized expressed DUX4 mRNAs in primary FSHD myoblasts. Polyclonal antibodies raised against specific DUX4 peptides detected the DUX4 protein in cells transfected with D4Z4 elements. DUX4 localizes in the nucleus of cells transfected with CMV-DUX4 expression vectors. A DUX4-related protein is endogenously expressed in nuclei of adult and fetal human rhabdomyosarcoma cell lines. Overexpression of DUX4 induces cell death, induces caspase 3/7 activity and alters emerin distribution at the nuclear envelope. We propose that DUX4-mediated cell death contributes to the pathogenic pathway in FSHD.
authors.affiliation: Laboratorio de Neurogenética, Instituto de Investigación, Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), Córdoba, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Kowaljow
authors.forename: Aline
authors.initials: A
authors.lastname: Marcowycz
authors.forename: Eugénie
authors.initials: E
authors.lastname: Ansseau
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Conde
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sauvage
authors.forename: Christel
authors.initials: C
authors.lastname: Mattéotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Arias
authors.forename: E Daniel
authors.initials: ED
authors.lastname: Corona
authors.forename: Nicolás G
authors.initials: NG
authors.lastname: Nuñez
authors.forename: Oberdan
authors.initials: O
authors.lastname: Leo
authors.forename: Ruddy
authors.initials: R
authors.lastname: Wattiez
authors.forename: Denise
authors.initials: D
authors.lastname: Figlewicz
authors.forename: Dalila
authors.initials: D
authors.lastname: Laoudj-Chenivesse
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
authors.forename: Frédérique
authors.initials: F
authors.lastname: Coppée
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Rosa
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D052097:Quadriceps Muscle / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D012208:Rhabdomyosarcoma; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C092710:emerin