title: Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy.
abstract: Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, which is recapitulated by collagen-VI-null (Col6a1(-/-)) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies, we performed a deep RNA profiling in both Col6a1(-/-)mice and patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1(-/-)(also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that might modify muscle damage pathogenesis.
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Scotton
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bovolenta
authors.affiliation: Ariadne Diagnostics, LLC, 9430 Key West Avenue, Suite 115, Rockville, MD 20850, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Schwartz
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Maria Sofia
authors.initials: MS
authors.lastname: Falzarano
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Martoni
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy Bambino Gesu' Children's Research Hospital, IRCCS, Rome 00146, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Passarelli
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Armaroli
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Hana
authors.initials: H
authors.lastname: Osman
authors.affiliation: Department of Neuroscience, University of Messina and Centro Clinico Nemo Sud, Messina 98125, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.affiliation: Department of Neuroscience, University of Messina and Centro Clinico Nemo Sud, Messina 98125, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.affiliation: Department of Neurosciences, University of Padova, Padova 35128, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.affiliation: Bambino Gesu' Children's Research Hospital, IRCCS, Rome 00146, Italy.
authors.forename: Adele
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authors.lastname: D'Amico
authors.affiliation: Bambino Gesu' Children's Research Hospital, IRCCS, Rome 00146, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Neri
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Selvatici
authors.affiliation: Department of Neurology, Regina Margherita Children's Hospital Turin, Torino 10126, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Boffi
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari 09124, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Maioli
authors.affiliation: Jon Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 7RU, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Jon Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 7RU, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.affiliation: Jon Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle NE1 7RU, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bushby
authors.affiliation: SCAI SuperComputing Applications and Innovation Department, Cineca, 00185 Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Castrignanò
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari 70121, Italy.
authors.forename: Graziano
authors.initials: G
authors.lastname: Pesole
authors.affiliation: Institute of Molecular Genetics, CNR-National Research Council of Italy, Bologna 40129, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.affiliation: SC Laboratory of Musculoskeletal Cell Biology, Rizzoli Orthopedic Institute, Bologna 40136, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Merlini
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova 35128, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Braghetta
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova 35128, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Department of Biomedical Science, University of Padova, Padova 35128, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1E 6BT, UK.
authors.forename: Reghan
authors.initials: R
authors.lastname: Foley
authors.affiliation: Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1E 6BT, UK.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1E 6BT, UK.
authors.forename: Irina
authors.initials: I
authors.lastname: Zaharieva
authors.affiliation: Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1E 6BT, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: University of Milan, Department of Biomedical Science for Health, Milan 20090, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Capitanio
authors.affiliation: University of Milan, Department of Biomedical Science for Health, Milan 20090, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
authors.affiliation: Ariadne Diagnostics, LLC, 9430 Key West Avenue, Suite 115, Rockville, MD 20850, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kotelnikova
authors.affiliation: Ariadne Genomics, LLC, 9430 Key West Avenue, Suite 113, Rockville, MD 20850, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Yuryev
authors.affiliation: Ariadne Diagnostics, LLC, 9430 Key West Avenue, Suite 115, Rockville, MD 20850, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lebowitz
authors.affiliation: Myology Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Xiping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Myology Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hodge
authors.affiliation: Myology Institute, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Karyn A
authors.initials: KA
authors.lastname: Esser
authors.affiliation: Medical Genetics Unit, Department of Medical Sciences, University of Ferrara, Ferrara 44121, Italy Dubowitz Neuromuscular Centre, University College London, Institute of Child Health, London WC1E 6BT, UK fla@unife.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferlini
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D057906:Circadian Clocks / Q000502:physiology*; D024142:Collagen Type VI / Q000235:genetics*; D003286:Contracture / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D008928:Mitochondria / Q000502:physiology*; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D012313:RNA / Q000032:analysis; D012598:Sclerosis / Q000235:genetics*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D024142:Collagen Type VI; D012313:RNA
keywords: Circadian rhythms; Interactome pathway; Myopathies; RNAseq