Clear Search sequence regions


  • alleles (2)
  • cerebellum (4)
  • exon (1)
  • GABA (2)
  • GABA receptor (1)
  • GABRA6 (5)
  • gabra6 protein, human (1)
  • genes (4)
  • human (3)
  • insulin (2)
  • intron (1)
  • isoforms (3)
  • minor (1)
  • mrna (1)
  • mrna isoforms (1)
  • plasma (1)
  • protein human (1)
  • protein- gene (1)
  • receptors (2)
  • regulates (1)
  • rna (12)
  • rs4454083 (3)
  • stem cells (1)
  • subunit (1)
  • synapses (2)
  • Sizes of these terms reflect their relevance to your search.

    Human disease-associated genetic variations often map to long non-coding RNA (lncRNA) genes; however, elucidation of their functional impact is challenging. We previously identified a new genetic variant rs4454083 (A/G) residing in exon of an uncharacterized lncRNA ARBAG that strongly associates with plasma levels of C-peptide, a hormone that regulates insulin bioavailability. On the opposite strand, rs4454083 also corresponds to an intron of a cerebellum-specific GABA receptor subunit gene GABRA6 that mediates strengthening of inhibitory synapses by insulin. Here, we show that alleles of rs4454083 modulate transcript levels of the antisense gene, ARBAG, which then controls the expression of the sense gene, GABRA6. Predisposing to low C-peptide, GG (a minor allele genotype across ethnicities) stabilizes ARBAG lncRNA causing higher transcript levels in cerebellum. ARBAG lncRNA abundance leads to cleavage of GABRA6 mRNA at the complementary region, resulting in a dysfunctional GABRA6 protein that would not be recruited for synapse strengthening. Together, our findings in human cerebellar cell-line and induced Pluripotent Stem Cells (iPSCs) demonstrate biological role of a novel lncRNA in determining the ratio of mRNA isoforms of a protein-coding gene and the ability of an embedded variant in modulating lncRNA stability leading to inter-individual differences in protein expression. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

    Citation

    Khushdeep Bandesh, Muneesh Pal, Abitha Balakrishnan, Pradeep Gautam, Punam Jha, Nikhil Tandon, Beena Pillai, Dwaipayan Bharadwaj. A novel antisense lncRNA, ARBAG harboring an RNA destabilizing GWAS variant for C-peptide dictates the transcript isoforms of GABRA6 in cerebellum. Human molecular genetics. 2023 Sep 16;32(19):2929-2939

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 37498167

    View Full Text