EVIDENCE FOR A REPRESSIVE FUNCTION OF THE LONG POLYGLUTAMINE TRACT IN THE HUMAN ANDROGEN RECEPTOR - POSSIBLE PATHOGENETIC RELEVANCE FOR THE (CAG)(N)-EXPANDED NEURONOPATHIES

We have reported that polyglutamine (polyGln)-expanded human androgen receptors (hAR) have reduced transactivational competence in transfected cells. We presumed that maximal hAR transactivation requires a normal-size polyGln tract, Here we report, however, that hAR transactivity and polyGln-tract length are related inversely: n = 0>12>20>40>50, Thus, a normal-size polyGln tract represses the transactivational competence of a polyGln-free hAR, and polyGln expansion increases that negative effect. This observation has pathogenetic implications for X-linked spinobulbar muscular atrophy (Kennedy syndrome), and possibly for the autosomal dominant central neuronopathies associated with (CAG)(n) expansion in the translated portion of four different genes.