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

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.

• Authors: David T Burns, Sandra Donkervoort, Juliane S Müller, Ellen Knierim, Diana Bharucha-Goebel, Eissa Ali Faqeih, Stephanie K Bell, Abdullah Y AlFaifi, Dorota Monies, Francisca Millan, Kyle Retterer, Sarah Dyack, Sara MacKay, Susanne Morales-Gonzalez, Michele Giunta, Benjamin Munro, Gavin Hudson, Mena Scavina, Laura Baker, Tara C Massini, Monkol Lek, Ying Hu, Daniel Ezzo, Fowzan S AlKuraya, Peter B Kang, Helen Griffin, A Reghan Foley, Markus Schuelke, Rita Horvath, Carsten G Bönnemann
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 102 Issue 5 Pg. 858-873 (05 03 2018) ISSN: 1537-6605 [Electronic] United States
• PMID: 29727687 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• EXOSC9 protein, human
• RNA-Binding Proteins
• Exosome Multienzyme Ribonuclease Complex

Topics

• Amino Acid Sequence
• Animals
• Atrophy
• Base Sequence
• Cerebellum (diagnostic imaging, pathology)
• Child, Preschool
• Exosome Multienzyme Ribonuclease Complex (chemistry, genetics)
• Exosomes (metabolism)
• Female
• Fibroblasts (metabolism, pathology)
• Gene Knockdown Techniques
• Genetic Variation
• Haplotypes (genetics)
• Humans
• Infant
• Male
• Motor Neurons (pathology)
• Muscle, Skeletal (metabolism)
• Pedigree
• RNA-Binding Proteins (chemistry, genetics)
• Spinal Cord (pathology)
• Zebrafish