Transcript mutations of the alpha regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes.
Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterised by diverse dysfunctions of immune effector cells, including proliferation and cytotoxicity. In T cells from patients with SLE, activity of type 1 protein kinase A isozymes is greatly reduced because of decreased e...
| Published in: | Lancet Vol. 360; no. 9336; pp. 842 - 850 |
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| Main Authors: | , , |
| Format: | research Journal Article |
| Published: |
Lancet
9/14/2002
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=136966954&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 136966954 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 01406736 LAN jtl: Lancet issn: 01406736 maglogo: N pubinfo: dt: 9/14/2002 vid: 360 iid: 9336 pid: 1297 pub: Lancet place: Philadelphia, Pennsylvania artinfo: ui: 136966954 136966954 NLM12243919 136966954 10.1016/s0140-6736(02)09966-x NLM12243919 136966954 ppf: 842 ppct: 8 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Transcript mutations of the alpha regulatory subunit of protein kinase A and up-regulation of the RNA-editing gene transcript in lupus T lymphocytes. aug: au: Laxminarayana, Dama Khan, Islam U Kammer, Gary affil: Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA sug: subj: RNA Transferases Mutation T Lymphocytes Metabolism Lupus Erythematosus, Systemic Genes Proteins Hydrolases DNA Nucleotides Male Sequence Analysis Prospective Studies Biochemical Phenomena Phosphotransferases Lupus Erythematosus, Systemic Immunology Female Human Adult Gene Expression Physiology Carrier Proteins Validation Studies Comparative Studies Evaluation Research Multicenter Studies Adult: 19-44 years Male Female ab: Background: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterised by diverse dysfunctions of immune effector cells, including proliferation and cytotoxicity. In T cells from patients with SLE, activity of type 1 protein kinase A isozymes is greatly reduced because of decreased expression of the alpha and beta regulatory subunits (RI alpha and RI beta). We aimed to identify a molecular mechanism or mechanisms for this isozyme deficiency by assessing occurrence of mutations in transcripts of the RI alpha subunit in patients with SLE.Methods: We cloned and sequenced cDNA of RI alpha and corresponding genomic DNA of the coding region to detect sequence changes from eight patients with SLE and six healthy controls. Because transcript editing is regulated by adenosine deaminases that act on RNA (ADAR), we quantified expression of ADAR1 transcripts in SLE and control T cells by competitive PCR.Findings: Sequence analyses of cDNA showed heterogeneous transcript mutations, including deletions, transitions, and transversions. We identified 1.22 x 10(-3)/bp transcript mutations in SLE T cells-a frequency 7.5 times higher than that in control T cells. By contrast, we identified no genomic mutations. Two hotspots were identified in the RI alpha subunit transcripts from SLE T cells, one located adjacent to a pseudosubstrate site of the RI alpha subunit and the other a component of the cAMP binding A domain. ADAR1 mRNA content was 3.5 times higher in SLE cells than in control T cells (p=0.001).Interpretation: An RNA-editing enzyme could be converting adenosine to inosine within double-stranded regions of RNA, resulting in transcript mutations. This process could be one mechanism resulting in mutations in the RI alpha subunit of type 1 protein kinase A. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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