Point mutations of
G protein genes that result in the constitutive activation of
G proteins have been described. Such mutations have been shown to occur in a number of
endocrine diseases. We have examined tissues from patients having more than one organ affected by an endocrine disorder and patients having separate distinct
endocrine diseases for
G protein gene mutations.
G protein genes encoding for Gs alpha and Gi2 alpha were examined for activating mutations at
codons 201 and 227 (Gs alpha) and
codons 179 and 205 (Gi2 alpha) using site-directed
oligonucleotide hybridization and direct sequencing of tissue
DNA amplified by polymerase chain reaction. Tissues from six patients were examined. The only mutation that was identified was at
codon 201 of Gs alpha (gsp), which encoded a change from
arginine to
cysteine. Patient 1 had the mutation in a
corticotroph adenoma, a
chemodectoma, and a nodular hyperplastic adrenal gland. patient 2 had the mutation in an extraadrenal
pheochromocytoma, but an adrenal gland with medullary
hyperplasia was wild-type. Patient 3 had an aggressive
corticotroph adenoma and developed Nelson's syndrome after bilateral
adrenalectomy. The
corticotroph adenoma was wild-type, but both hyperplastic adrenal glands had the mutation. Patient 4 had the mutation in a
parathyroid adenoma and in two hyperplastic parathyroid glands. Patient 5 had the mutation in both a primary and a metastatic
pheochromocytoma. Patient 6 had the mutation in a
parathyroid adenoma and also in histologically normal thyroid and parathyroid tissue. Leukocyte
DNA was examined from five patients and was found to be wild-type in all cases. We conclude that
G protein gene mutations occur in a wider range of endocrine conditions than has been recognized hereto. In addition, the presence of gsp mutations in different endocrine disorders in the same patient is suggestive of a common underlying etiology.