PUBLICATION
Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy
- Authors
- Burns, D.T., Donkervoort, S., Müller, J.S., Knierim, E., Bharucha-Goebel, D., Faqeih, E.A., Bell, S.K., AlFaifi, A.Y., Monies, D., Millan, F., Retterer, K., Dyack, S., MacKay, S., Morales-Gonzalez, S., Giunta, M., Munro, B., Hudson, G., Scavina, M., Baker, L., Massini, T.C., Lek, M., Hu, Y., Ezzo, D., AlKuraya, F.S., Kang, P.B., Griffin, H., Foley, A.R., Schuelke, M., Horvath, R., Bönnemann, C.G.
- ID
- ZDB-PUB-180508-10
- Date
- 2018
- Source
- American journal of human genetics 102: 858-873 (Journal)
- Registered Authors
- Keywords
- RNA metabolism, cerebellar atrophy, exosome, neurodegenerative diseases, spinal muscular atrophy
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Atrophy
- Base Sequence
- Cerebellum/diagnostic imaging
- Cerebellum/pathology*
- Child, Preschool
- Exosome Multienzyme Ribonuclease Complex/chemistry
- Exosome Multienzyme Ribonuclease Complex/genetics*
- Exosomes/metabolism*
- Female
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Gene Knockdown Techniques
- Genetic Variation*
- Haplotypes/genetics
- Humans
- Infant
- Male
- Motor Neurons/pathology*
- Muscle, Skeletal/metabolism
- Pedigree
- RNA-Binding Proteins/chemistry
- RNA-Binding Proteins/genetics*
- Spinal Cord/pathology*
- Zebrafish
- PubMed
- 29727687 Full text @ Am. J. Hum. Genet.
Citation
Burns, D.T., Donkervoort, S., Müller, J.S., Knierim, E., Bharucha-Goebel, D., Faqeih, E.A., Bell, S.K., AlFaifi, A.Y., Monies, D., Millan, F., Retterer, K., Dyack, S., MacKay, S., Morales-Gonzalez, S., Giunta, M., Munro, B., Hudson, G., Scavina, M., Baker, L., Massini, T.C., Lek, M., Hu, Y., Ezzo, D., AlKuraya, F.S., Kang, P.B., Griffin, H., Foley, A.R., Schuelke, M., Horvath, R., Bönnemann, C.G. (2018) Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy. American journal of human genetics. 102:858-873.
Abstract
The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161∗). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping