title: Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.
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.
authors.affiliation: Department of Neurology, University of California, Los Angeles, California, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Wan
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.forename: Hafsa
authors.initials: H
authors.lastname: Mamsa
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Hong
authors.forename: Derek W
authors.initials: DW
authors.lastname: Leong
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Michael S
authors.initials: MS
authors.lastname: Salman
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kornberg
authors.forename: Manuel
authors.initials: M
authors.lastname: Castro-Gago
authors.forename: María-Jesús
authors.initials: MJ
authors.lastname: Sobrido
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sanefuji
authors.forename: Perry B
authors.initials: PB
authors.lastname: Shieh
authors.forename: Noriko
authors.initials: N
authors.lastname: Salamon
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Kim
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Zugen
authors.initials: Z
authors.lastname: Chen
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Jen
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D063326:Exosome Multienzyme Ribonuclease Complex; D055354:Exosomes; D055785:Gene Knockdown Techniques; D006801:Humans; D009046:Motor Neurons; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009849:Olivopontocerebellar Atrophies / Q000235:genetics* / Q000473:pathology; D011149:Pons / Q000473:pathology*; D012313:RNA / Q000032:analysis; D016601:RNA-Binding Proteins / Q000235:genetics*; D013127:Spinal Nerves / Q000473:pathology; D015027:Zebrafish / Q000196:embryology
chemical_list: C571397:EXOSC3 protein, human; D016601:RNA-Binding Proteins; D012313:RNA; D063326:Exosome Multienzyme Ribonuclease Complex