International Immunology, Vol. 12, No. 11, 1521-1529,
November 2000
© 2000 Japanese Society for Immunology
mRNA mutations of type I protein kinase A regulatory subunit 
in T lymphocytes of a subject with systemic lupus erythematosus
Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
Correspondence to: G. M. Kammer (E-mail: gmkammer{at}wfubmc.edu) or D. Laxminarayana (E-mail: dlaxmina{at}wfubmc.edu)
Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by multiple T lymphocyte immune effector dysfunctions. Protein kinase A (PKA) isozymes contribute to the regulation of T cell immune effector functions. In SLE T cells, there is a profound deficiency of PKA-I isozyme activity characterized by both reduced RI
transcript and RI protein levels. To identify a molecular mechanism(s) for this isozyme deficiency, we utilized single-strand conformation polymorphism (SSCP) analysis to detect structural changes in the cDNA. Of 10 SLE subjects, cDNAs from a single subject revealed a shifted band. Sequence analyses demonstrated that a shifted SSCP band from SLE T cells carried heterogeneous transcript mutations, including deletions, transitions and transversions. Most of these transcript mutations are clustered adjacent to GAGAG motifs and CT repeats—regions that are susceptible to transcript editing and/or molecular misreading. By contrast, no genomic mutations were identified. These results suggest the occurrence of mRNA editing and/or defective function of RNA polymerase in a subject with SLE. Mutant RI transcripts are pathophysiolgically significant, for they can encode diverse, aberrant RI isoforms, including truncated, dominant-negative subunits, resulting in deficient PKA-I activity. We propose that deficient PKA-I isozyme activity contributes to the pathogenesis of SLE by hindering effective signal transduction and impairing T cell effector functions.
Keywords: autoimmunity, immune dysfunction, mutations in gene transcripts
Transmitting editor: M. Feldmann
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