2. Academic Validation
  3. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia

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

  • Nat Commun. 2014 Jul 3;5:4287. doi: 10.1038/ncomms5287.
Veronika Boczonadi 1,  Juliane S Müller 1,  Angela Pyle 1,  Jennifer Munkley 1,  Talya Dor 2,  Jade Quartararo 3,  Ileana Ferrero 3,  Veronika Karcagi 4,  Michele Giunta 5,  Tuomo Polvikoski 6,  Daniel Birchall 7,  Agota Princzinger 8,  Yuval Cinnamon 9,  Susanne Lützkendorf 10,  Henriett Piko 4,  Mojgan Reza 5,  Laura Florez 11,  Mauro Santibanez-Koref 5,  Helen Griffin 5,  Markus Schuelke 10,  Orly Elpeleg 2,  Luba Kalaydjieva 11,  Hanns Lochmüller 5,  David J Elliott 5,  Patrick F Chinnery 5,  Shimon Edvardson 2,  Rita Horvath 5
Affiliations

Affiliations

  • 1 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2].
  • 2 The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel.
  • 3 Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, Parma 43124, Italy.
  • 4 Department of Molecular Genetics and Diagnostics, NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary.
  • 5 Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
  • 6 Department of Pathology, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
  • 7 Neuroradiology Department, Regional Neurosciences Centre, Queen Victoria Road, Newcastle upon Tyne NE1 4PL, UK.
  • 8 Department of Paediatrics, Josa Andras Hospital, Szent Istvan utca 6, Nyiregyhaza 4400, Hungary.
  • 9 1] The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel [2] Department of Poultry and Aquaculture Sciences, Institute of Animal Science, Agricultural Research Organization, The Volcani Center, P.O.Box 6, Bet Dagan 50250, Israel.
  • 10 Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany.
  • 11 Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia.
PMID: 24989451 DOI: 10.1038/ncomms5287
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.

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