Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients

Michael Levin, Sang Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number4436.2
JournalF1000Research
Volume3
DOIs
StatePublished - Sep 18 2014

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RNA-Binding Proteins
Nuclear Proteins
Multiple Sclerosis
Nucleotides
Epitopes
Karyopherins
Cell Nucleus Active Transport
Autoantigens
Amino Acid Substitution
DNA Sequence Analysis
Cytoplasm
Substitution reactions
Immunoglobulin G
Apoptosis
Amino Acids

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients. / Levin, Michael; Lee, Sang.

In: F1000Research, Vol. 3, 4436.2, 18.09.2014.

Research output: Contribution to journalArticle

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