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

Veronika Boczonadi, Juliane S. Müller, Angela Pyle, Jennifer Munkley, Talya Dor, Jade Quartararo, Ileana Ferrero, V. Karcagi, Michele Giunta, Tuomo Polvikoski, Daniel Birchall, Agota Princzinger, Yuval Cinnamon, Susanne Lützkendorf, Henriett Piko, Mojgan Reza, Laura Florez, Mauro Santibanez-Koref, Helen Griffin, Markus SchuelkeOrly Elpeleg, Luba Kalaydjieva, Hanns Lochmüller, David J. Elliott, Patrick F. Chinnery, Shimon Edvardson, Rita Horvath

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number4287
JournalNature Communications
Volume5
DOIs
Publication statusPublished - Jul 3 2014

Fingerprint

AU Rich Elements
ribonucleic acids
atrophy
Exosomes
Myelin Proteins
Spinal Muscular Atrophy
myelin
metabolism
mutations
Metabolism
Neurodegenerative diseases
proteins
Motor Neuron Disease
Messenger RNA
Mutation
Corpus Callosum
causes
Oligodendroglia
Neurology
Zebrafish

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Boczonadi, V., Müller, J. S., Pyle, A., Munkley, J., Dor, T., Quartararo, J., ... Horvath, R. (2014). EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nature Communications, 5, [4287]. https://doi.org/10.1038/ncomms5287

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. / Boczonadi, Veronika; Müller, Juliane S.; Pyle, Angela; Munkley, Jennifer; Dor, Talya; Quartararo, Jade; Ferrero, Ileana; Karcagi, V.; Giunta, Michele; Polvikoski, Tuomo; Birchall, Daniel; Princzinger, Agota; Cinnamon, Yuval; Lützkendorf, Susanne; Piko, Henriett; Reza, Mojgan; Florez, Laura; Santibanez-Koref, Mauro; Griffin, Helen; Schuelke, Markus; Elpeleg, Orly; Kalaydjieva, Luba; Lochmüller, Hanns; Elliott, David J.; Chinnery, Patrick F.; Edvardson, Shimon; Horvath, Rita.

In: Nature Communications, Vol. 5, 4287, 03.07.2014.

Research output: Contribution to journalArticle

Boczonadi, V, Müller, JS, Pyle, A, Munkley, J, Dor, T, Quartararo, J, Ferrero, I, Karcagi, V, Giunta, M, Polvikoski, T, Birchall, D, Princzinger, A, Cinnamon, Y, Lützkendorf, S, Piko, H, Reza, M, Florez, L, Santibanez-Koref, M, Griffin, H, Schuelke, M, Elpeleg, O, Kalaydjieva, L, Lochmüller, H, Elliott, DJ, Chinnery, PF, Edvardson, S & Horvath, R 2014, 'EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia', Nature Communications, vol. 5, 4287. https://doi.org/10.1038/ncomms5287
Boczonadi, Veronika ; Müller, Juliane S. ; Pyle, Angela ; Munkley, Jennifer ; Dor, Talya ; Quartararo, Jade ; Ferrero, Ileana ; Karcagi, V. ; Giunta, Michele ; Polvikoski, Tuomo ; Birchall, Daniel ; Princzinger, Agota ; Cinnamon, Yuval ; Lützkendorf, Susanne ; Piko, Henriett ; Reza, Mojgan ; Florez, Laura ; Santibanez-Koref, Mauro ; Griffin, Helen ; Schuelke, Markus ; Elpeleg, Orly ; Kalaydjieva, Luba ; Lochmüller, Hanns ; Elliott, David J. ; Chinnery, Patrick F. ; Edvardson, Shimon ; Horvath, Rita. / EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. In: Nature Communications. 2014 ; Vol. 5.
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