Key result
Multiple sclerosis patients harbored novel somatic single nucleotide variants in the TPNO-1 binding domain of hnRNP A1 that were absent in healthy controls and caused cytoplasmic mis-localization and cellular apoptosis.
Case-Control (n=20)
No
Novel somatic SNVs in hnRNP A1 found in MS patients cause protein mislocalization, reduced transportin-1 binding, and cellular apoptosis, suggesting a potential pathogenic mechanism in multiple sclerosis.
Supports hnRNP A1 variants as potential MS mechanism; hypothesis-generating from animal data and requires human validation.
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.
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Lee et al. (2014) conducted a case-control in Multiple sclerosis (n=20). Somatic single nucleotide variants in hnRNP A1 vs. Healthy controls (wild type hnRNP A1) was evaluated on Presence of somatic single nucleotide variants in the TPNO-1 binding domain of hnRNP A1-M9. Multiple sclerosis patients harbored novel somatic single nucleotide variants in the TPNO-1 binding domain of hnRNP A1 that were absent in healthy controls and caused cytoplasmic mis-localization and cellular apoptosis.
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