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

Jijun Wan, Michael Yourshaw, Hafsa Mamsa, Sabine Rudnik-Schöneborn, Manoj P. Menezes, Ji Eun Hong, Derek W. Leong, Jan Senderek, Michael S. Salman, David Chitayat, Pavel Seeman, Arpad Von Moers, Luitgard Graul-Neumann, Andrew J. Kornberg, Manuel Castro-Gago, María Jesús Sobrido, Masafumi Sanefuji, Perry B. Shieh, Noriko Salamon, Ronald C. KimHarry V. Vinters, Zugen Chen, Klaus Zerres, Monique M. Ryan, Stanley F. Nelson, Joanna C. Jen

Research output: Contribution to journalArticlepeer-review

180 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)704-708
Number of pages5
JournalNature genetics
Issue number6
Publication statusPublished - Jun 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics


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