title: MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia.
abstract: Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and a decrease in the synthesis of the encoded protein IKAP (also known as ELP1). Small non-coding RNAs known as microRNAs (miRNAs) are important post-transcriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP loss, we examined expression of miRNAs in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from five control individuals and five FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative PCR (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs had been previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP, supporting a potential interaction between NOVA1 and IKAP. Taken together, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be a regulator of FD pathophysiology.
authors.affiliation: CRN2M-UMR7286, Aix-Marseille Université, CNRS, Faculté de Médecine Nord, Marseille 13344, Cedex 15, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Hervé
authors.affiliation: CRN2M-UMR7286, Aix-Marseille Université, CNRS, Faculté de Médecine Nord, Marseille 13344, Cedex 15, France el-cherif.ibrahim@univ-amu.fr.
authors.forename: El Chérif
authors.identifier: 0000-0003-3973-7862
authors.initials: EC
authors.lastname: Ibrahim
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D004402:Dysautonomia, Familial / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D000090682:Neuro-Oncological Ventral Antigen; D009830:Olfactory Bulb / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; C000594513:NOVA1 protein, human; D000090682:Neuro-Oncological Ventral Antigen; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D035602:Transcriptional Elongation Factors
keywords: ELP1; Familial dysautonomia; IKAP; MicroRNA; NOVA1; Stem cell