title: Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy.
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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.|Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Giunta
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, 91120 Jerusalem, Israel.|Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Shimon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Yaobo
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Aurora
authors.initials: A
authors.lastname: Gomez-Duran
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Veronika
authors.initials: V
authors.lastname: Boczonadi
authors.affiliation: The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, 91120 Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.|Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Juliane S
authors.initials: JS
authors.lastname: Müller
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK Rita.Horvath@ncl.ac.uk.|Institute of Genetic Medicine, Newcastle University, Central Parkway, NE1 3BZ, Newcastle upon Tyne, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D055354:Exosomes / Q000235:genetics; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016601:RNA-Binding Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015027:Zebrafish / Q000378:metabolism
chemical_list: C571397:EXOSC3 protein, human; C000596172:RBM7 protein, human; D016601:RNA-Binding Proteins; C456279:EXOSC8 protein, human; D063326:Exosome Multienzyme Ribonuclease Complex