NELSONS SYNDROME-ASSOCIATED WITH A SOMATIC FRAME-SHIFT MUTATION IN THE GLUCOCORTICOID RECEPTOR GENE

Nelson's syndrome is the appearance and/or progression of ACTH-secreti ng pituitary macroadenomas in patients who had previously undergone bi lateral adrenalectomy for Gushing's disease. Extremely high plasma ACT H levels and aggressive neoplastic growth might be explained by the la ck of appropriate glucocorticoid negative feedback due to defective gl ucocorticoid signal transduction. To study the glu cocorticoid recepto r (GR) gene in Nelson's syndrome, DNA was extracted from pituitary ade nomas and leukocytes of four patients with this condition and amplifie d by PGR for direct sequence analysis. In one of the tumors, a heteroz ygous mutation, consisting of an insertion of a thymine between comple mentary DNA nucleotides 1188 and 1189, was found in exon 2. This frame -shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a funct ioning receptor protein from the defective allele. The mutation was no t detected in the sequence of the GR gene in the patient's leukocyte D NA, indicating a somatic origin. By lowering the receptor number in tu morous cells, this defect might have caused local resistance to negati ve glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistan ce syndrome. P53 protein accumulation, previously reported in 60% of c orticotropinomas, could not be detected in any of the four pituitary t umors examined by immunohistochemistry. We suggest that a somatic GR d efect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.