POLYMORPHISM IN THE I-ALPHA(1) GERM-LINE TRANSCRIPT REGULATORY REGIONAND IGA PRODUCTIVITY IN PATIENTS WITH IGA NEPHROPATHY

Enhanced in vivo and in vitro production of IgA has been reported in p atients with IgA nephropathy (IgAN) and their family members. It is ge nerally considered that IgA1 is a prominent subclass of IgA in IgAN, A lthough genetic mechanisms of IgA class snitch recombination in IgAN h ave been studied enthusiastically, the critical factors that induce Ig A1-specific class switching in IgAN have yet to be elucidated. A large body of data indicates that the germ-line transcript of Tg constant r egion (C-H) genes that precedes actual class switching has regulatory effects on class switch recombination. To analyze structural abnormali ties in the I alpha(1) germ-line transcript regulatory gene, a region about 1000 bp long located upstream of I alpha(1) exons was surveyed b y the PCR-single strand conformation polymorphism method, and the poly morphism detected was confirmed by subsequent DNA sequencing. Three ho t spots for point mutation were detected upstream of the promoter regi on of the I alpha(1) germ-line transcript, and the mutations were obse rved more frequently in patients than in controls. Patients with the m utations showed higher levels of serum IgA and higher in vitro IgA syn thesis. In the luciferase assay, the regulatory gene with the mutation s showed a potent effect for induction of the I alpha(1) germ-line tra nscript. The polymorphism in the I alpha(1) regulatory region possibly causes enhanced IgA production in some patients with IgAN.