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

Author

Listed:
  • Veronika Boczonadi

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Juliane S. Müller

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Angela Pyle

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Jennifer Munkley

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Talya Dor

    (Hadassah– Hebrew University Medical Center)

  • Jade Quartararo

    (University of Parma, Parco Area delle Scienze 11A)

  • Ileana Ferrero

    (University of Parma, Parco Area delle Scienze 11A)

  • Veronika Karcagi

    (NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary)

  • Michele Giunta

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Tuomo Polvikoski

    (Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality)

  • Daniel Birchall

    (Regional Neurosciences Centre, Queen Victoria Road, Newcastle upon Tyne NE1 4PL, UK)

  • Agota Princzinger

    (Josa Andras Hospital, Szent Istvan utca 6, Nyiregyhaza 4400, Hungary)

  • Yuval Cinnamon

    (Hadassah– Hebrew University Medical Center
    Institute of Animal Science, Agricultural Research Organization, The Volcani Center, P.O.Box 6, Bet Dagan 50250, Israel)

  • Susanne Lützkendorf

    (Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany)

  • Henriett Piko

    (NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary)

  • Mojgan Reza

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Laura Florez

    (Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia)

  • Mauro Santibanez-Koref

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Helen Griffin

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Markus Schuelke

    (Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany)

  • Orly Elpeleg

    (Hadassah– Hebrew University Medical Center)

  • Luba Kalaydjieva

    (Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia)

  • Hanns Lochmüller

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • David J. Elliott

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Patrick F. Chinnery

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

  • Shimon Edvardson

    (Hadassah– Hebrew University Medical Center)

  • Rita Horvath

    (Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway)

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.

Suggested Citation

  • Veronika Boczonadi & Juliane S. Müller & Angela Pyle & Jennifer Munkley & Talya Dor & Jade Quartararo & Ileana Ferrero & Veronika Karcagi & Michele Giunta & Tuomo Polvikoski & Daniel Birchall & Agota , 2014. "EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia," Nature Communications, Nature, vol. 5(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5287
    DOI: 10.1038/ncomms5287
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    Cited by:

    1. Kenzui Taniue & Anzu Sugawara & Chao Zeng & Han Han & Xinyue Gao & Yuki Shimoura & Atsuko Nakanishi Ozeki & Rena Onoguchi-Mizutani & Masahide Seki & Yutaka Suzuki & Michiaki Hamada & Nobuyoshi Akimits, 2024. "The MTR4/hnRNPK complex surveils aberrant polyadenylated RNAs with multiple exons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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