ANALYSIS OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR) GENE INJAPANESE PATIENTS WITH CONGENITAL LIPOID ADRENAL-HYPERPLASIA

Genomic DNA from 19 Japanese patients with congenital lipoid adrenal h yperplasia (lipoid CAH) representing 16 different families was examine d to identify the genetic alterations of steroidogenic acute regulator y protein (StAR), Ten of 19 patients had a 46,XX karyotype and nine ha d a 46,XY karyotype, Six of the 46,XX patients have experienced sponta neous pubertal changes including breast development and irregular mens truation whereas none of the 46,XY subjects displayed pubertal changes , Eight different mutations were identified. Sixteen patients were eit her homozygotes or compound heterozygotes for the Q258X mutation. The seven other mutations identified were 189delG, 246insG, 564del13bp, 83 8delA, Q212X, A218V and M225T, The 189delG, 246insG, 546del13bp and Q2 12X mutants encode truncated proteins, COS-1 cells transfected with ex pression vectors encoding cDNAs for the mutant StAR proteins which aff ect the C-terminus, 838delA, A218V and Q258X, exhibited no steroidogen esis enhancing activity, However, the M225T mutant retained some stero idogenic activity, The patient with the M225T mutation had late onset of this disorder and some capacity to secrete testosterone in response to hCG. These findings suggest: (i) that the Q258X mutation can be us ed as a genetic marker for the screening of Japanese for lipoid CAH, ( ii) that the C-terminus of StAR plays an important role in the protein 's activity and (iii) that there are differences in the extent of func tional impairment of the testis and ovaries in lipoid CAH.