Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.

TitleMutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
Publication TypeJournal Article
Year of Publication2012
AuthorsWan, J, Yourshaw M, Mamsa H, Rudnik-Schöneborn S, Menezes MP, Hong JE, Leong DW, Senderek J, Salman MS, Chitayat D, Seeman P, von Moers A, Graul-Neumann L, Kornberg AJ, Castro-Gago M, Sobrido M-J, Sanefuji M, Shieh PB, Salamon N, Kim RC, Vinters HV, Chen Z, Zerres K, Ryan MM, Nelson SF, Jen JC
JournalNature genetics
Volume44
Issue6
Pagination704-8
Date Published2012 Jun
ISSN1546-1718
KeywordsAnimals, Cerebellum, Exosomes, Gene Knockdown Techniques, Humans, Motor Neurons, Nerve Degeneration, Olivopontocerebellar Atrophies, pons, RNA, RNA-Binding Proteins, Spinal Nerves, Zebrafish
Abstract

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.

DOI10.1111/j.1465-3362.2010.00271.x
Alternate JournalNat. Genet.