Key result
Genomic DNA sequencing revealed nine novel somatic single nucleotide variants in the hnRNP A1 gene in multiple sclerosis patients that were absent in healthy controls, leading to cytoplasmic mis-localization and cellular apoptosis in vitro.
Case-Control (n=20)
No
Novel somatic SNVs in hnRNP A1 found in MS patients lead to protein mislocalization, reduced transportin-1 binding, and cellular apoptosis, suggesting a potential pathogenic mechanism in MS.
May implicate hnRNP A1 variants in MS apoptosis; leaves open validation as biomarker or target.
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 novel somatic single nucleotide variants (SNVs) resulting in amino acid substitutions within the TPNO-1 binding domain and MS IgG epitope of hnRNP A1-M9. Genomic DNA sequencing revealed nine novel somatic single nucleotide variants in the hnRNP A1 gene in multiple sclerosis patients that were absent in healthy controls, leading to cytoplasmic mis-localization and cellular apoptosis in vitro.
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