Case report| Volume 22, P153-156, May 2018

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Dysregulation of NRXN1 by mutant MIR8485 leads to calcium overload in pre-synapses inducing neurodegeneration in Multiple sclerosis


      • 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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        • Alló M.
        • Agirre E.
        • Bessonov S.
        • Bertucci P.
        • Gómez Acuña L.
        • et al.
        Argonaute-1 binds transcriptional enhancers and controls constitutive and alternative splicing in human cells.
        PNAS. 2014; 111: 15622-15629
        • Atasoy D.
        • Schoch S.
        • Ho A.
        • Nadasy K.A.
        • et al.
        Deletion of CASK in mice is lethal and impairs synaptic function.
        Proc. Natl. Acad. Sci. USA. 2007; 104: 2525
        • Barca-Mayo O.
        • Lu Q.R.
        Fine-tuning oligodendrocyte development by microRNAs.
        Front. Neurosci. 2012; 6: 13
        • Biederer T.
        • Südhof T.C.
        Mints as adaptors. Direct binding to neurexins and recruitment ofmunc18.
        J. Biol. Chem. 2000; 275 (10): 39803-39806
        • Browne P.
        • Chandraratna D.
        • Angood C.
        • Tremlett H.
        Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity.
        Neurology. 2014; 983: 1022-1024
        • Chang X.
        • Wang K.
        wANNOVAR annotating genetic variants for personal genomes via the web.
        J. Med. Genet. 2012; 49: 433-436
        • Craig A.M.
        • Kang Y.
        Neurexin–neuroligin signaling in synapse development.
        Curr. Opin. Neurobiol. 2007; 17: 43
        • Ebers G.C.
        • Bulman D.E.
        • Sadovnick A.D.
        • Paty D.W.
        • Warren S.
        • Hader W.
        • et al.
        A population‐based study of multiple sclerosis in twins.
        New Engl. J. Med. 1986; 315: 1638-1642
        • Fan Z.
        • Chen X.
        • Chen R.
        Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression.
        Genomics. 2014; 103: 76-82
        • Faria O.D.
        • Moore C.S.
        • Kennedy T.E.
        • et al.
        MicroRNA dysregulation in multiple sclerosis.
        Front. Genet. 2012; 3: 311
        • Gorman C.O.
        • Lucas R.
        • Taylor B.
        Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms.
        Int. J. Mol. Sci. 2012; 13: 11718-11752
        • Hata Y.
        • Butz S.
        • Südhof T.C.
        CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins.
        J. Neurosci. 1996; 16: 2488-2494
        • Kakalacheva K.
        • MünzC
        • Lünemann J.D.
        Viral triggers of multiple sclerosis.
        Biochim. Biophys. Acta (BBA) – Mol. Basis Dis. 2011; 1812: 132-140
        • LaFerla F.M.
        Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease.
        Nat. Rev. Neurosci. 2002; 3: 862-872
        • Loma I.
        • Heyman R.
        Multiple sclerosis: pathogenesis and treatment.
        Curr. Neuropharmacol. 2011; 9: 409-416
        • Lublin F.D.
        New multiple sclerosis phenotypic classification.
        Eur. Neurol. 2014; 72
        • Meister G.
        Argonaute proteins: functional insights and emerging roles.
        Nat. Rev. Genet. 2013; 14: 447-459
        • Missler M.
        • ZhangW
        • Rohlmann A.
        • Kattenstroth G.
        α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis.
        Nature. 2003; 423: 939-948
        • Nielsen N.M.
        • Westergaard T.
        • Rostgaard K.
        • Frisch M.
        • Hjalgrim H.
        • Wohlfahrt J.
        Familial risk of multiple sclerosis: a nationwide cohort study.
        Am. J. Epidemiol. 2005; 162: 774-778
        • Nikitin A.
        • Egorov S.
        • Daraselia N.
        • et al.
        Pathway studio—the analysis and navigation of molecular networks.
        Bioinformatics. 2003; 19: 2155-2157
        • Pham P.H.
        • Shipman W.J.
        • Erikson G.A.
        • Schork N.J.
        • Torkamani A.
        Scripps genome ADVISER: annotation and distributed variant interpretation SERver.
        PLoS One. 2015; 10: e0116815
      1. QIAGEN. Ingenuity® Variant Analysis™ software (〈〉). QIAGEN Redwood City.

        • Retterer K.
        • Juusola J.
        • Cho M.T.
        • Vitazka P.
        • Millan F.
        • Gibellini F.
        • et al.
        Clinical application of whole-exome sequencing across clinical indications.
        Genet. Med. 2016; 18: 696-704
        • Santo-Domingo J.
        • Demaurex N.
        Calcium uptake mechanisms of mitochondria.
        Biochim. Biophys. Acta (BBA)–Bioenerg. 2010; 1796: 907-912
        • Singhal B.S.
        • Advani H.
        Multiple sclerosis in India: an overview.
        Ann. Indian Acad. Neurol. 2015; 18: S2-S5
        • Veerappa A.M.
        • Saldanha M.
        • Padakannaya P.
        • et al.
        Family-based genome-wide copy number scan identifies five new genes of dyslexia involved in dendritic spinal plasticity.
        J. Hum. Genet. 2013; 58: 539-547
        • Veerappa A.M.
        • Murthy M.N.
        • Vishweswaraiah S.
        • et al.
        Copy number variations burden on miRNA genes reveals layers of complexities involved in the regulation of pathways and phenotypic expression.
        PLoS One. 2014; 9: e90391
        • Wei Y.
        • Lim L.
        • Wang L.
        • Song J.
        Inter-domain interactions of TDP-43 as decoded by NMR.
        Biochem. Biophys. Res. Commun. 2016; 44: 614-619
        • Xue Y.
        • Ankala A.
        • Wilcox W.R.
        • Hegde M.R.
        Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing.
        Genet. Med. 2015; 17: 444-451