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EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

Lookup NU author(s): Dr Veronika Boczonadi, Dr Juliane Mueller, Dr Angela Pyle, Dr Jennifer Munkley, Michele Giunta, Dr Tuomo Polvikoski, Dr Daniel Birchall, Dr Mojgan Reza, Dr Mauro Santibanez Koref, Dr Helen GriffinORCiD, Professor Hanns Lochmuller, Professor David Elliott, Professor Patrick Chinnery, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Publication metadata

Author(s): Boczonadi V, Muller JS, Pyle A, Munkley J, Dor T, Quartararo J, Ferrero I, Karcagi V, Giunta M, Polvikoski T, Birchall D, Princzinger A, Cinnamon Y, Lutzkendorf S, Piko H, Reza M, Florez L, Santibanez-Koref M, Griffin H, Schuelke M, Elpeleg O, Kalaydjieva L, Lochmuller H, Elliott DJ, Chinnery PF, Edvardson S, Horvath R

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2014

Volume: 5

Online publication date: 03/07/2014

Acceptance date: 03/06/2014

Date deposited: 29/10/2014

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/ncomms5287


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Funder referenceFunder name
UK NIHR Biomedical Research Centre
Medical Research Council (MRC) Centre for Neuromuscular Diseases Biobank Newcastle
Mitochondrial European Educational Training (MEET)
UK Parkinson's Disease Society
309548European Research Council
98482Medical Research Council UK
305121European Union Seventh Framework Programme (FP7)
305444European Union Seventh Framework Programme (FP7)
A-2011-63Einstein Stiftung Berlin, Germany
G1000848Medical Research Council (UK)
G1002274Medical Research Council UK
GGP11011Fondazione Telethon (Italy)
PG12-34Prostate Cancer UK
101876/Z/13/ZWellcome Trust