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Deep RNA profiling identified CLOCK and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Lookup NU author(s): Elena Martoni, Professor Hanns Lochmuller, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby


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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.

Publication metadata

Author(s): Scotton C, Bovolenta M, Schwartz E, Falzarano MS, Martoni E, Passarelli C, Armaroli A, Osman H, Rodolico C, Messina S, Pegoraro E, D'Amico A, Bertini E, Gualandi F, Neri M, Selvatici R, Boffi P, Maioli MA, Lochmuller H, Straub V, Bushby K, Castrignano T, Pesole G, Sabatelli P, Merlini L, Braghetta P, Bonaldo P, Bernardi P, Foley R, Cirak S, Zaharieva I, Muntoni F, Capitanio D, Gelfi C, Kotelnikova E, Yuryev A, Lebowitz M, Zhang XP, Hodge BA, Esser KA, Ferlini A

Publication type: Article

Publication status: Published

Journal: Journal of Cell Science

Year: 2016

Volume: 129

Issue: 8

Pages: 1671-1684

Print publication date: 15/04/2016

Online publication date: 04/03/2016

Acceptance date: 16/02/2016

ISSN (print): 0021-9533

ISSN (electronic): 1477-9137

Publisher: The Company of Biologists Ltd


DOI: 10.1242/jcs.175927


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Funder referenceFunder name
Biomedical Research Centre at Great Ormond Street Hospital
MRC Neuromuscular Centre at UCL
Great Ormond Street Hospital Children's Charity
Muscular Dystrophy Campaign Centre Grant at UCL
241665BIO-NMD European Union Seventh Framework Programme
305444RD-Connect EU project
AR066082National Institutes of Health
GGP08017Fondazione Telethon
GUP11007Fondazione Telethon