Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

TitleVariants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.
Publication TypeJournal Article
Year of Publication2018
AuthorsBurns, DT, Donkervoort, S, Müller, JS, Knierim, E, Bharucha-Goebel, D, Faqeih, EAli, Bell, SK, AlFaifi, AY, Monies, D, Millan, F, Retterer, K, Dyack, S, MacKay, S, Morales-Gonzalez, S, Giunta, M, Munro, B, Hudson, G, Scavina, M, Baker, L, Massini, TC, Lek, M, Hu, Y, Ezzo, D, Alkuraya, FS, Kang, PB, Griffin, H, A Foley, R, Schuelke, M, Horvath, R, Bönnemann, CG
JournalAm J Hum Genet
Date Published2018 05 03
KeywordsAmino Acid Sequence, Animals, Atrophy, Base Sequence, Cerebellum, Child, Preschool, Exosome Multienzyme Ribonuclease Complex, Exosomes, Female, Fibroblasts, Gene Knockdown Techniques, Genetic Variation, Haplotypes, Humans, Infant, Male, Motor Neurons, Muscle, Skeletal, Pedigree, RNA-Binding Proteins, Spinal Cord, Zebrafish

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID29727687
PubMed Central IDPMC5986733
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
G1000848 / / Medical Research Council / United Kingdom
MR/N027302/1 / / Medical Research Council / United Kingdom
201064/Z/16/Z / / Wellcome Trust / United Kingdom
309548 / / European Research Council / International
MR/N025431/1 / / Medical Research Council / United Kingdom
203105/Z/16/Z / / Wellcome Trust / United Kingdom
109915/Z/15/Z / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom