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Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration
- Source :
- Nature genetics, vol 44, iss 6, Nature genetics
- Publication Year :
- 2012
- Publisher :
- eScholarship, University of California, 2012.
-
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.
- Subjects :
- Pediatric Research Initiative
Exosome complex
Pontocerebellar hypoplasia
RNA-binding protein
Biology
Neurodegenerative
Exosomes
Medical and Health Sciences
Article
03 medical and health sciences
0302 clinical medicine
Rare Diseases
Clinical Research
Cerebellum
Pons
medicine
Genetics
Animals
Humans
2.1 Biological and endogenous factors
Cerebellar hypoplasia
Zebrafish
030304 developmental biology
Motor Neurons
Pediatric
0303 health sciences
Messenger RNA
Exosome Multienzyme Ribonuclease Complex
Neurosciences
RNA
RNA-Binding Proteins
Biological Sciences
medicine.disease
Non-coding RNA
Exosome component 3
Spinal Nerves
Gene Knockdown Techniques
Nerve Degeneration
Neurological
Olivopontocerebellar Atrophies
Congenital Structural Anomalies
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature genetics, vol 44, iss 6, Nature genetics
- Accession number :
- edsair.doi.dedup.....7faa49cde015ed4cfaa4d712b3e92368