- •We report the consequences of novel and rare damaging mutations in MIR8485 and NRXN1.
- •Dysregulation of NRXN1 by mutant miR-8485, leads to overexpression of NRXN1, triggering influx of Ca2+ altering Ca2+ homeostasis.
- •Sustained increase in Ca2+ may contribute to oxidative stress and cell death.
- •Under pathological conditions of cellular Ca2+ overload, mitochondrial Ca2+ uptake may trigger pathological states leading to neurodegeneration.
- •The identified genes add up to existing mutational spectrum of Multiple sclerosis, helping in devising new therapeutic approaches in treatment, management and prevention”.
To identify Damaging mutations in microRNAs (miRNAs) and 3’ untranslated regions (UTRs) of target genes to establish Multiple sclerosis (MS) disease pathway.
Female aged 16, with Relapsing Remitting Multiple sclerosis (RRMS) was reported with initial symptoms of blurred vision, severe immobility, upper and lower limb numbness and backache. Whole Exome Sequencing (WES) and disease pathway analysis was performed to identify mutations in miRNAs and UTRs.
We identified Deleterious/Damaging multibase mutations in MIR8485 and NRXN1. miR-8485 was found carrying frameshift homozygous deletion of bases CA, while NRXN1 was found carrying nonframeshift homozygous substitution of bases CT to TC in exon 8 replacing Serine with Leucine.
Mutations in miR-8485 and NRXN1 was found to alter calcium homeostasis and NRXN1/NLGN1 cell adhesion molecule binding affinities. The miR-8485 mutation leads to overexpression of NRXN1 altering pre-synaptic Ca2+ homeostasis, inducing neurodegeneration.
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Published online: April 09, 2018
Accepted: April 6, 2018
Received in revised form: January 13, 2018
Received: September 17, 2017
© 2018 Elsevier B.V. All rights reserved.