Activating mutations of the stimulatory G protein in the McCune-Albright syndrome

Lee S. Weinstein, Andrew Shenker, Pablo V. Gejman, Allen M. Spiegel, Eitan Friedman, Allen M. Spiegel

Research output: Contribution to journalArticle

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Abstract

Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the α subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hybridization. Results. We detected one of two activating mutations within exon 8 of the Gsα gene in tissues from all four patients, including affected endocrine organs (gonads, adrenal glands, thyroid, and pituitary) and tissues not classically involved in the McCune-Albright syndrome. In two of the patients histidine was substituted for arginine at position 201 of Gsα, and in the other two patients cysteine was substituted for the same arginine residue. In each patient the proportion of cells affected varied from tissue to tissue. In two endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Conclusions. Mutations within exon 8 of the Gsα gene that result in increased activity of the Gs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome. Somatic mutation of this gene early in embryogenesis could result in the mosaic population of normal and mutant-bearing tissues that may underlie the clinical manifestations of this disease.

Original languageEnglish (US)
Pages (from-to)1688-1695
Number of pages8
JournalNew England Journal of Medicine
Volume325
Issue number24
StatePublished - Dec 12 1991
Externally publishedYes

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Polyostotic Fibrous Dysplasia
GTP-Binding Proteins
Mutation
Cyclic AMP
Exons
Genes
Arginine
DNA
Alleles
Endocrine Glands
Denaturing Gradient Gel Electrophoresis
Gonads
Pituitary Neoplasms
Missense Mutation
Adrenal Glands
Histidine
Oligonucleotides
Embryonic Development
Cysteine
Signal Transduction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Weinstein, L. S., Shenker, A., Gejman, P. V., Spiegel, A. M., Friedman, E., & Spiegel, A. M. (1991). Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. New England Journal of Medicine, 325(24), 1688-1695.

Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. / Weinstein, Lee S.; Shenker, Andrew; Gejman, Pablo V.; Spiegel, Allen M.; Friedman, Eitan; Spiegel, Allen M.

In: New England Journal of Medicine, Vol. 325, No. 24, 12.12.1991, p. 1688-1695.

Research output: Contribution to journalArticle

Weinstein, LS, Shenker, A, Gejman, PV, Spiegel, AM, Friedman, E & Spiegel, AM 1991, 'Activating mutations of the stimulatory G protein in the McCune-Albright syndrome', New England Journal of Medicine, vol. 325, no. 24, pp. 1688-1695.
Weinstein LS, Shenker A, Gejman PV, Spiegel AM, Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. New England Journal of Medicine. 1991 Dec 12;325(24):1688-1695.
Weinstein, Lee S. ; Shenker, Andrew ; Gejman, Pablo V. ; Spiegel, Allen M. ; Friedman, Eitan ; Spiegel, Allen M. / Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. In: New England Journal of Medicine. 1991 ; Vol. 325, No. 24. pp. 1688-1695.
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abstract = "Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, caf{\'e} au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the α subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hybridization. Results. We detected one of two activating mutations within exon 8 of the Gsα gene in tissues from all four patients, including affected endocrine organs (gonads, adrenal glands, thyroid, and pituitary) and tissues not classically involved in the McCune-Albright syndrome. In two of the patients histidine was substituted for arginine at position 201 of Gsα, and in the other two patients cysteine was substituted for the same arginine residue. In each patient the proportion of cells affected varied from tissue to tissue. In two endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Conclusions. Mutations within exon 8 of the Gsα gene that result in increased activity of the Gs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome. Somatic mutation of this gene early in embryogenesis could result in the mosaic population of normal and mutant-bearing tissues that may underlie the clinical manifestations of this disease.",
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AU - Spiegel, Allen M.

AU - Friedman, Eitan

AU - Spiegel, Allen M.

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N2 - Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the α subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hybridization. Results. We detected one of two activating mutations within exon 8 of the Gsα gene in tissues from all four patients, including affected endocrine organs (gonads, adrenal glands, thyroid, and pituitary) and tissues not classically involved in the McCune-Albright syndrome. In two of the patients histidine was substituted for arginine at position 201 of Gsα, and in the other two patients cysteine was substituted for the same arginine residue. In each patient the proportion of cells affected varied from tissue to tissue. In two endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Conclusions. Mutations within exon 8 of the Gsα gene that result in increased activity of the Gs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome. Somatic mutation of this gene early in embryogenesis could result in the mosaic population of normal and mutant-bearing tissues that may underlie the clinical manifestations of this disease.

AB - Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, café au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the α subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and allele-specific oligonucleotide hybridization. Results. We detected one of two activating mutations within exon 8 of the Gsα gene in tissues from all four patients, including affected endocrine organs (gonads, adrenal glands, thyroid, and pituitary) and tissues not classically involved in the McCune-Albright syndrome. In two of the patients histidine was substituted for arginine at position 201 of Gsα, and in the other two patients cysteine was substituted for the same arginine residue. In each patient the proportion of cells affected varied from tissue to tissue. In two endocrine organs, the highest proportion of mutant alleles was found in regions of abnormal cell proliferation. Conclusions. Mutations within exon 8 of the Gsα gene that result in increased activity of the Gs protein and increased cAMP formation are present in various tissues of patients with the McCune-Albright syndrome. Somatic mutation of this gene early in embryogenesis could result in the mosaic population of normal and mutant-bearing tissues that may underlie the clinical manifestations of this disease.

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