期刊
NATURE GENETICS
卷 44, 期 6, 页码 704-U134出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2254
关键词
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资金
- NIH/National Eye Institute (NEI) [R01 EY015311, NINDS R01 NS064183]
- Deutsche Forschungsgemeinschaft [Ru-746/1-1]
- IZKF Aachen [N5-4]
- Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence
- Internal Grant Agency of the Ministry of Health of the Czech Republic [NS 10552-3]
- Xunta de Galicia-Plan Galego de InvestigaCion, Desenvolvemento e Innovacion Tecnoloxica (INCITE) [10PXIB9101280PR]
RNA exosomes are multi-subunit complexes conserved throughout evolution(1) 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(2). 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)(3-6). 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.
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