Identification of a Mutation in the Gene Encoding the α Subunit of the Stimulatory G Protein of Adenylyl Cyclase in McCune-Albright Syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 89; no. 11; pp. 5152 - 5156
• Main Authors: Schwindinger, William F., Francomano, Clair A., Levine, Michael A.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.06.1992; National Acad Sciences
• Subjects: adenylyl cyclase; Adenylyl Cyclases - metabolism; Alleles; alpha subunit; Amino Acid Sequence; association; Base Sequence; Biological and medical sciences; Diseases of the osteoarticular system; DNA; Enzyme Activation; Exons; Fibrous Dysplasia, Polyostotic - genetics; Gels; genes; Genetic mutation; Genomics; GTP-Binding Proteins - genetics; guanine nucleotide-binding protein; Humans; Lesions; Leukocytes; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; man; McCune-Albright syndrome; Medical sciences; Middle Aged; Molecular Sequence Data; Mosaicism; Mutation; nucleotide sequence; Oligodeoxyribonucleotides - chemistry; Polymerase Chain Reaction; Endocrinopathy; Human; GTP; Skin disease; Enzyme; Diseases of the osteoarticular system; Stimulation; Adenylate cyclase; Binding protein; Gene; Pseudohyperparathyroidism; Alpha-Peptide chain; Albright disease; Mutation; Osteochondrodysplasia; G protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.11.5152

McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, cafe-au-lait lesions, and a variety of endocrine disorders, including precocious puberty, hyperthyroidism, hypercortisolism, growth hormone excess, and hyperprolactinemia. The diverse metabolic abnormalities seen in MAS share the involvement of cells that respond to extracellular signals through activation of the hormone-sensitive adenylyl cyclase system (EC 4.6.1.1). Mutations that lead to constitutive activation of Gsα, the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase activity, have been identified in a subset of human growth hormone-secreting pituitary tumors and human thyroid tumors. We report here the identification of a mutation in the gene encoding Gsα in a patient with MAS. Denaturing gradient gel electrophoresis was used to analyze amplified DNA fragments including exon 8 or exon 9 of the Gsα gene. In one subject with MAS a G-to-A transition was found in exon 8 of one of the two alleles encoding Gsα. This single-base substitution results in the replacement of arginine by histidine at position 201 of the mature Gsα protein. Semiquantitative analysis of amplified DNA indicated that the mutant allele was less prevalent than the wild-type allele in peripheral leukocytes and was present in very low levels in skin. These findings support the previous contention that the segmental distribution and variable expression of the cutaneous, skeletal, and endocrine manifestations of MAS reflect an underlying somatic mosaicism. Further, these results suggest that the molecular basis of MAS is a postzygotic mutation in Gsα that causes constitutive activation of adenylyl cyclase.