RRC ID 49692
Author Giunta M, Edvardson S, Xu Y, Schuelke M, Gomez-Duran A, Boczonadi V, Elpeleg O, Müller JS, Horvath R.
Title Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy.
Journal Hum Mol Genet
Abstract The exosome complex is the most important RNA processing machinery within the cell. Mutations in its subunits EXOSC8 and EXOSC3 cause pontocerebellar hypoplasia, spinal muscular atrophy (SMA) and central nervous system demyelination. We present a patient with SMA-like phenotype carrying a homozygous mutation in RBM7-a subunit of the nuclear exosome targeting (NEXT) complex-which is known to bind and carry specific subtypes of coding and non-coding RNAs to the exosome. The NEXT complex with other protein complexes is responsible for the substrate specificity of the exosome. We performed RNA-sequencing (RNA-seq) analysis on primary fibroblasts of patients with mutations in EXOSC8 and RBM7 and gene knock-down experiments using zebrafish as a model system. RNA-seq analysis identified significantly altered expression of 62 transcripts shared by the two patient cell lines. Knock-down of rbm7, exosc8 and exosc3 in zebrafish showed a common pattern of defects in motor neurons and cerebellum. Our data indicate that impaired RNA metabolism may underlie the clinical phenotype by fine tuning gene expression which is essential for correct neuronal differentiation.
Volume 25(14)
Pages 2985-2996
Published 2016-7-15
DOI 10.1093/hmg/ddw149
PII ddw149
PMID 27193168
PMC PMC5181591
MeSH Animals Cerebellum / metabolism Cerebellum / pathology Disease Models, Animal Exosome Multienzyme Ribonuclease Complex / genetics* Exosomes / genetics Humans Motor Neurons / metabolism Motor Neurons / pathology Muscular Atrophy, Spinal / genetics* Muscular Atrophy, Spinal / metabolism Muscular Atrophy, Spinal / pathology Mutation RNA-Binding Proteins / genetics* Sequence Analysis, RNA Zebrafish / metabolism
IF 5.101
Times Cited 19
Zebrafish Tg(CM-isl1:GFP)