{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T09:26:36Z","timestamp":1740129996807,"version":"3.37.3"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T00:00:00Z","timestamp":1690416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Department of Science and Technology, Government of India","award":["PURSE II CDST\/SR\/PURSE PHASE II\/11"],"award-info":[{"award-number":["PURSE II CDST\/SR\/PURSE PHASE II\/11"]}]},{"DOI":"10.13039\/501100001412","name":"Council of Scientific and Industrial Research","doi-asserted-by":"crossref","award":["MLP2008","BSC0122"],"award-info":[{"award-number":["MLP2008","BSC0122"]}],"id":[{"id":"10.13039\/501100001412","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.1093\/hmg\/ddad119","type":"journal-article","created":{"date-parts":[[2023,7,27]],"date-time":"2023-07-27T13:41:01Z","timestamp":1690465261000},"page":"2929-2939","source":"Crossref","is-referenced-by-count":0,"title":["A novel antisense lncRNA, <i>ARBAG<\/i> harboring an RNA destabilizing GWAS variant for C-peptide dictates the transcript isoforms of <i>GABRA6<\/i> in cerebellum"],"prefix":"10.1093","volume":"32","author":[{"given":"Khushdeep","family":"Bandesh","sequence":"first","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR) , Ghaziabad 201002, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muneesh","family":"Pal","sequence":"additional","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abitha","family":"Balakrishnan","sequence":"additional","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradeep","family":"Gautam","sequence":"additional","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3270-5526","authenticated-orcid":false,"given":"Punam","family":"Jha","sequence":"additional","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR) , Ghaziabad 201002, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikhil","family":"Tandon","sequence":"additional","affiliation":[{"name":"All India Institute of Medical Sciences Department of Endocrinology and Metabolism, , New Delhi 110029, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beena","family":"Pillai","sequence":"additional","affiliation":[{"name":"CSIR-Institute of Genomics and Integrative Biology , Delhi 110025, India"},{"name":"Academy of Scientific and Innovative Research (AcSIR) , Ghaziabad 201002, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5268-8482","authenticated-orcid":false,"given":"Dwaipayan","family":"Bharadwaj","sequence":"additional","affiliation":[{"name":"Jawaharlal Nehru University Systems Genomics Laboratory, School of Biotechnology, , New Delhi 110067, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,7,27]]},"reference":[{"key":"2023091911314482200_ref1","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1002\/oby.21137","article-title":"C-peptide modifies leptin and visfatin secretion in human adipose tissue","volume":"23","author":"Garcia-Serrano","year":"2015","journal-title":"Obesity (Silver Spring)"},{"key":"2023091911314482200_ref2","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1111\/dom.12477","article-title":"Efficacy of a long-acting C-peptide analogue against peripheral neuropathy in streptozotocin-diabetic mice","volume":"17","author":"Jolivalt","year":"2015","journal-title":"Diabetes Obes. 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Neurosci."},{"key":"2023091911314482200_ref16","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/35051086","article-title":"Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance","volume":"409","author":"Brickley","year":"2001","journal-title":"Nature"},{"key":"2023091911314482200_ref17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fncel.2018.00010","article-title":"Missense gamma-aminobutyric acid receptor polymorphisms are associated with reaction time, motor time, and ethanol effects in vivo","volume":"12","author":"Garc\u00eda-Mart\u00edn","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"2023091911314482200_ref18","doi-asserted-by":"crossref","first-page":"12887","DOI":"10.1038\/s41598-017-12776-8","article-title":"A new stress sensor and risk factor for suicide: the T allele of the functional genetic variant in the GABRA6 gene","volume":"7","author":"Gonda","year":"2017","journal-title":"Sci. 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Disord."},{"key":"2023091911314482200_ref23","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1046\/j.1460-9568.1999.00421.x","article-title":"Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice","volume":"11","author":"Korpi","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"2023091911314482200_ref24","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/sj.ijo.0802022","article-title":"Allelic variants in the GABA(A)alpha6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion","volume":"26","author":"Rosmond","year":"2002","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"2023091911314482200_ref25","article-title":"Proinsulin C-peptide research at"},{"key":"2023091911314482200_ref26","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.bbrc.2009.12.125","article-title":"Oligomerization and insulin interactions of proinsulin C-peptide: threefold relationships to properties of insulin","volume":"391","author":"J\u00f6rnvall","year":"2010","journal-title":"Biochem. Biophys. Res. 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Med."},{"key":"2023091911314482200_ref29","doi-asserted-by":"crossref","first-page":"9676","DOI":"10.1523\/JNEUROSCI.0513-15.2015","article-title":"\u03b16-containing GABAA receptors are the principal mediators of inhibitory synapse strengthening by insulin in cerebellar granule cells","volume":"35","author":"Accardi","year":"2015","journal-title":"J. Neurosci."},{"key":"2023091911314482200_ref30","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0065-1281(82)80080-9","article-title":"C-peptide immunoreactive neurons in human brain","volume":"70","author":"Dorn","year":"1982","journal-title":"Acta Histochem."},{"year":"2022","key":"2023091911314482200_ref31","article-title":"Type 2 Diabetes Knowledge Portal"},{"key":"2023091911314482200_ref32","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2021.731712","article-title":"Single nucleotide polymorphisms of porcine lncMGPF regulate meat production traits by affecting RNA stability","volume":"9","author":"Lv","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"2023091911314482200_ref33","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1002\/ajmg.a.32053","article-title":"Cartilage hair hypoplasia mutations that lead to RMRP promoter inefficiency or RNA transcript instability","volume":"143","author":"Nakashima","year":"2007","journal-title":"Am. J. Med. Genet."},{"key":"2023091911314482200_ref34","doi-asserted-by":"crossref","first-page":"3668","DOI":"10.2174\/1381612827666210315145254","article-title":"Harnessing the potential of long non-coding RNAs to manage metabolic diseases","volume":"27","author":"Bandesh","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"2023091911314482200_ref35","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41576-021-00427-8","article-title":"From genotype to phenotype: genetics of mammalian long non-coding RNAs in vivo","volume":"23","author":"Andergassen","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"2023091911314482200_ref36","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3389\/fncel.2014.00047","article-title":"Non-coding RNA interact to regulate neuronal development and function","volume":"8","author":"Iyengar","year":"2014","journal-title":"Front. Cell. 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Mol."},{"key":"2023091911314482200_ref40","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1038\/nsmb.3302","article-title":"Insertion of an Alu element in a lncRNA leads to primate-specific modulation of alternative splicing","volume":"23","author":"Hu","year":"2016","journal-title":"Nat. Struct. Mol."},{"key":"2023091911314482200_ref41","doi-asserted-by":"crossref","first-page":"22083","DOI":"10.1016\/S0021-9258(18)54535-X","article-title":"Inhibition of c-erbA mRNA splicing by a naturally occurring antisense RNA","volume":"266","author":"Munroe","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2023091911314482200_ref42","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1000529","article-title":"A flexible and accurate genotype imputation method for the next generation of genome-wide association studies","volume":"5","author":"Howie","year":"2009","journal-title":"PLoS Genet."},{"key":"2023091911314482200_ref43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"1000 Genomes Project Consortium","year":"2015","journal-title":"Nature"},{"key":"2023091911314482200_ref44","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1004234","article-title":"A general approach for haplotype phasing across the full spectrum of relatedness","volume":"10","author":"O'Connell","year":"2014","journal-title":"PLoS Genet."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad119\/51116823\/ddad119.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/19\/2929\/51611071\/ddad119.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/19\/2929\/51611071\/ddad119.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T11:32:44Z","timestamp":1695123164000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/19\/2929\/7232174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,27]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,7,27]]},"published-print":{"date-parts":[[2023,9,16]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad119","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"type":"print","value":"0964-6906"},{"type":"electronic","value":"1460-2083"}],"subject":[],"published-other":{"date-parts":[[2023,10,1]]},"published":{"date-parts":[[2023,7,27]]}}}