RRC ID 33637
Author 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.
Title EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.
Journal Nat Commun
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.
Volume 5
Pages 4287
Published 2014-7-3
DOI 10.1038/ncomms5287
PII ncomms5287
PMID 24989451
PMC PMC4102769
MeSH Agenesis of Corpus Callosum / genetics* Amino Acid Sequence Animals Cerebellum / abnormalities* Cerebellum / pathology Cerebral Cortex / pathology Developmental Disabilities / genetics Developmental Disabilities / pathology Exosome Multienzyme Ribonuclease Complex / genetics* Female Fungal Proteins / metabolism Gene Expression Gene Knockdown Techniques Hereditary Central Nervous System Demyelinating Diseases / genetics* Hereditary Central Nervous System Demyelinating Diseases / pathology Homozygote Humans Infant Male Molecular Sequence Data Nervous System Malformations / genetics* Nervous System Malformations / pathology RNA-Binding Proteins / genetics* Sequence Analysis, DNA Spinal Muscular Atrophies of Childhood / genetics* Syndrome Zebrafish
IF 11.878
Times Cited 11
Zebrafish isl1:GFP/rw0