title: Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy.
abstract: Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a non-pathogenic D4Z4 array (n = 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic transcript was detected in FSHD biopsies but also in controls. Importantly, in FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. Our study is the first to examine fetuses carrying an FSHD-linked genotype and reveals an extensive dysregulation of several muscle-specific and 4q35 genes at early development stage at a distance from any muscle defect. Overall, our work suggests that even if FSHD is an adult-onset muscular dystrophy, the disease might also involve early molecular defects arising during myogenesis or early differentiation.
authors.affiliation: The authors wish it to be known that in their opinion the first two and the last two authors should be regarded as joint authors.
authors.forename: Natacha
authors.initials: N
authors.lastname: Broucqsault
authors.forename: Julia
authors.initials: J
authors.lastname: Morere
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Gaillard
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.forename: Julia
authors.initials: J
authors.lastname: Torrents
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Salort-Campana
authors.forename: André
authors.initials: A
authors.lastname: Maues De Paula
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.forename: Carla
authors.initials: C
authors.lastname: Fernandez
authors.forename: Anne Laure
authors.initials: AL
authors.lastname: Chesnais
authors.forename: Maxime
authors.initials: M
authors.lastname: Ferreboeuf
authors.forename: Laure
authors.initials: L
authors.lastname: Sarda
authors.forename: Henry
authors.initials: H
authors.lastname: Dufour
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.forename: Karine
authors.initials: K
authors.lastname: Nguyen
authors.forename: Frédérique
authors.initials: F
authors.lastname: Magdinier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roche
mesh_terms: D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005333:Fetus / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D024510:Muscle Development / Q000235:genetics*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology*; D017570:MyoD Protein / Q000235:genetics; D009928:Organ Specificity; D019683:Penetrance; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein