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A pproximately 40% of growth hormone–secreting pituitary adenomas have somatic mutations in the GNAS1 gene (the so-called gsp oncogene). These mutations at codon 201 or codon 227 constitutively activate the α subunit of the adenylate cyclase–stimulating G protein G_s. GNAS1 is subject to a complex pattern of genomic imprinting, its various promoters directing the production of maternally, paternally, and biallelically derived gene products. Transcripts encoding G_sα are biallelically derived in most human tissues. Despite this, we show here that in 21 out of 22 gsp-positive somatotroph adenomas, the mutation had occurred on the maternal allele. To investigate the reason for this allelic bias, we also analyzed GNAS1 imprinting in the normal adult pituitary and found that G_sα is monoallelically expressed from the maternal allele in this tissue. We further show that this monoallelic expression of G_sα is frequently relaxed in somatotroph tumors, both in those that have gsp mutations and in those that do not. These findings imply a possible role for loss of G_sα imprinting during pituitary somatotroph tumorigenesis and also suggest that G_sα imprinting is regulated separately from that of the other GNAS1 products, NESP55 and XLαs, imprinting of which is retained in these tumors.