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Abstract
Some somatic single nucleotide variants (SNVs) are thought to be pathogenic, leading to neurological disease. We hypothesized that heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an autoantigen associated with multiple sclerosis (MS) would contain SNVs. MS patients develop antibodies to hnRNP A1 (293-304), an epitope within the M9 domain (AA (268-305)) of hnRNP A1. M9 is hnRNP A1's nucleocytoplasmic transport domain, which binds transportin-1 (TPNO-1) and allows for hnRNP A1's transport into and out of the nucleus. Genomic DNA sequencing of M9 revealed nine novel SNVs that resulted in an amino acid substitution in MS patients that were not present in controls. SNVs occurred within the TPNO-1 binding domain (hnRNP A1 (268-289)) and the MS IgG epitope (hnRNP A1 (293-304)), within M9. In contrast to the nuclear localization of wild type (WT) hnRNP A1, mutant hnRNP A1 mis-localized to the cytoplasm, co-localized with stress granules and caused cellular apoptosis. Whilst WT hnRNP A1 bound TPNO-1, mutant hnRNP A1 showed reduced TPNO-1 binding. These data suggest SNVs in hnRNP A1 might contribute to pathogenesis of MS.
Highlights
Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) in humans, whose pathogenesis remains unknown
We discovered novel somatic genomic DNA single nucleotide variants (SNVs) in MS patients
Three additional SNVs (c.793A>G, p.N265D; c.787T>C, p.F263L) included amino acids within the prion-like domain (PrLD) - M9 overlap region (AA263-267), which bind TPNO-145. These variants were in a region of hnRNP A1 that are adjacent to mutations shown to cause amyotrophic lateral sclerosis (ALS) (p.D262V, p.N267A)
Summary
Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) in humans, whose pathogenesis remains unknown. A number of genetic and immune studies indicate dysregulated immune responses as contributors to the pathogenesis of MS1–7. Genetic analyses show an association of MS with major histocompatibility complex (MHC) Class II human leukocyte antigen (HLA)-DRB-1 and single nucleotide polymorphisms (SNPs) related to immune function[1,2,8]. Both Th1/Th17 CD4+ T-lymphocytes and immunoglobulins appear to have a causative role[1,2,9]. Immunoglobulin G (IgG) responses to myelin and non-myelin targets have differentiated some MS patients from healthy controls[9,10,11]. Nonmyelin antigens that are targets for immunoglobulins isolated from MS patients include neurofilaments, axonal neurofascin and RNA binding proteins, including heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1)[9,12,13,14,15,16]
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