Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia

Genomic DNA from 19 Japanese patients with congenital lipoid adrenalhyperplasia (lipoid CAH) representing 16 different families was examined toidentify the genetic alterations of steroidogenic acute regulatory protein(StAR). Ten of 19 patients had a 46,XX karyotype and nine had a 46,XYkaryotype. Six of the 46,XX patients have experienced spontaneous pubertalchanges including breast development and irregular menstruation whereasnone of the 46,XY subjects displayed pubertal changes. Eight differentmutations were identified. Sixteen patients were either homozygotes orcompound heterozygotes for the Q258X mutation. The seven other mutationsidentified were 189delG, 246insG, 564del13bp, 838delA, Q212X, A218V andM225T. The 189delG, 246insG, 546del13bp and Q212X mutants encode truncatedproteins. COS-1 cells transfected with expression vectors encoding cDNAsfor the mutant StAR proteins which affect the C-terminus, 838delA, A218Vand Q258X, exhibited no steroidogenesis enhancing activity. However, theM225T mutant retained some steroidogenic activity. The patient with theM225T mutation had late onset of this disorder and some capacity to secretetestosterone in response to hCG. These findings suggest: (i) that the Q258Xmutation can be used as a genetic marker for the screening of Japanese forlipoid CAH, (ii) that the C-terminus of StAR plays an important role in theprotein's activity and (iii) that there are differences in the extent offunctional impairment of the testis and ovaries in lipoid CAH.