RRC ID 54992
Author Burns DT, Donkervoort S, Müller JS, Knierim E, Bharucha-Goebel D, Faqeih EA, 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, Foley AR, Schuelke M, Horvath R, Bönnemann CG.
Title Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.
Journal Am. J. Hum. Genet.
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.
Volume 102(5)
Pages 858-873
Published 2018-5-3
DOI 10.1016/j.ajhg.2018.03.011
PII S0002-9297(18)30100-9
PMID 29727687
PMC PMC5986733
MeSH 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
IF 9.924
Zebrafish Tg(CM-isl1:GFP)