title: EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.
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.
authors.affiliation: 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2].
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.affiliation: 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2].
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.affiliation: 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2].
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: 1] Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK [2].
authors.forename: Jennifer
authors.initials: J
authors.lastname: Munkley
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Talya
authors.initials: T
authors.lastname: Dor
authors.affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, Parma 43124, Italy.
authors.forename: Jade
authors.initials: J
authors.lastname: Quartararo
authors.affiliation: Department of Life Sciences, University of Parma, Parco Area delle Scienze 11A, Parma 43124, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.affiliation: Department of Molecular Genetics and Diagnostics, NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary.
authors.forename: Veronika
authors.initials: V
authors.lastname: Karcagi
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Giunta
authors.affiliation: Department of Pathology, Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Polvikoski
authors.affiliation: Neuroradiology Department, Regional Neurosciences Centre, Queen Victoria Road, Newcastle upon Tyne NE1 4PL, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Birchall
authors.affiliation: Department of Paediatrics, Josa Andras Hospital, Szent Istvan utca 6, Nyiregyhaza 4400, Hungary.
authors.forename: Agota
authors.initials: A
authors.lastname: Princzinger
authors.affiliation: 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.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Cinnamon
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lützkendorf
authors.affiliation: Department of Molecular Genetics and Diagnostics, NIEH, Albert Florian ut 2-6, Budapest 1097, Hungary.
authors.forename: Henriett
authors.initials: H
authors.lastname: Piko
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Reza
authors.affiliation: Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Florez
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Charité-Platz 1, 10117 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Western Australian Institute for Medical Research/Centre for Medical Research, The University of Western Australia, 35 Stirling Highway Crawley, Western Australia 6009 Perth, Australia.
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliott
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah- Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Shimon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D005260:Female; D005656:Fungal Proteins / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics*; D013577:Syndrome; D015027:Zebrafish
chemical_list: D005656:Fungal Proteins; D016601:RNA-Binding Proteins; C456279:EXOSC8 protein, human; D063326:Exosome Multienzyme Ribonuclease Complex