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

Am J Hum Genet. 2018 May 3;102(5):858-873. doi: 10.1016/j.ajhg.2018.03.011.

David T Burns ¹, Sandra Donkervoort ², Juliane S Müller ¹, Ellen Knierim ³, Diana Bharucha-Goebel ⁴, Eissa Ali Faqeih ⁵, Stephanie K Bell ⁶, Abdullah Y AlFaifi ⁵, Dorota Monies ⁷, Francisca Millan ⁸, Kyle Retterer ⁸, Sarah Dyack ⁹, Sara MacKay ¹⁰, Susanne Morales-Gonzalez ³, Michele Giunta ¹, Benjamin Munro ¹, Gavin Hudson ¹, Mena Scavina ¹¹, Laura Baker ¹², Tara C Massini ¹³, Monkol Lek ¹⁴, Ying Hu ², Daniel Ezzo ², Fowzan S AlKuraya ⁷, Peter B Kang ⁶, Helen Griffin ¹, A Reghan Foley ², Markus Schuelke ³, Rita Horvath ¹⁵, Carsten G Bönnemann ²

Affiliations

1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
2 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
3 Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
4 Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Division of Neurology, Children's National Medical Center, Washington, DC 20010, USA.
5 Section of Medical Genetics, Department of Pediatric Subspecialties, Children's Specialized Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
6 Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
7 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
8 GeneDx, Gaithersburg, MD 20877, USA.
9 Departments of Pediatrics and Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.
10 Maritime Medical Genetics Service, IWK Health Centre, Halifax, NS B3K 6R8, Canada.
11 Division of Neurology, Nemours/DuPont Hospital for Children, Wilmington, DE 19803, USA.
12 Division of Genetics, Nemours/DuPont Hospital for Children, Wilmington, DE 19803, USA.
13 Department of Radiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
14 Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 01242, USA.
15 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: rita.horvath@ncl.ac.uk.

PMID: 29727687 DOI: 10.1016/j.ajhg.2018.03.011

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.

Keywords

RNA metabolism; cerebellar atrophy; exosome; neurodegenerative diseases; spinal muscular atrophy.

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