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. 1992 Jun 1;89(11):5152–5156. doi: 10.1073/pnas.89.11.5152

Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome.

W F Schwindinger 1, C A Francomano 1, M A Levine 1
PMCID: PMC49247  PMID: 1594625

Abstract

McCune-Albright syndrome (MAS) is characterized by polyostotic fibrous dysplasia, café-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 Gs alpha, 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 Gs alpha in a patient with MAS. Denaturing gradient gel electrophoresis was used to analyze amplified DNA fragments including exon 8 or exon 9 of the Gs alpha gene. In one subject with MAS a G-to-A transition was found in exon 8 of one of the two alleles encoding Gs alpha. This single-base substitution results in the replacement of arginine by histidine at position 201 of the mature Gs alpha 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 Gs alpha that causes constitutive activation of adenylyl cyclase.

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Selected References

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  1. Burton F. H., Hasel K. W., Bloom F. E., Sutcliffe J. G. Pituitary hyperplasia and gigantism in mice caused by a cholera toxin transgene. Nature. 1991 Mar 7;350(6313):74–77. doi: 10.1038/350074a0. [DOI] [PubMed] [Google Scholar]
  2. Chitayat D., Friedman J. M., Johnston M. M. Hypomelanosis of Ito--a nonspecific marker of somatic mosaicism: report of case with trisomy 18 mosaicism. Am J Med Genet. 1990 Mar;35(3):422–424. doi: 10.1002/ajmg.1320350320. [DOI] [PubMed] [Google Scholar]
  3. Cuttler L., Jackson J. A., Saeed uz-Zafar M., Levitsky L. L., Mellinger R. C., Frohman L. A. Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. J Clin Endocrinol Metab. 1989 Jun;68(6):1148–1154. doi: 10.1210/jcem-68-6-1148. [DOI] [PubMed] [Google Scholar]
  4. Feuillan P. P., Shawker T., Rose S. R., Jones J., Jeevanram R. K., Nisula B. C. Thyroid abnormalities in the McCune-Albright syndrome: ultrasonography and hormonal studies. J Clin Endocrinol Metab. 1990 Dec;71(6):1596–1601. doi: 10.1210/jcem-71-6-1596. [DOI] [PubMed] [Google Scholar]
  5. Foster C. M., Ross J. L., Shawker T., Pescovitz O. H., Loriaux D. L., Cutler G. B., Jr, Comite F. Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome. J Clin Endocrinol Metab. 1984 Jun;58(6):1161–1165. doi: 10.1210/jcem-58-6-1161. [DOI] [PubMed] [Google Scholar]
  6. Freissmuth M., Gilman A. G. Mutations of GS alpha designed to alter the reactivity of the protein with bacterial toxins. Substitutions at ARG187 result in loss of GTPase activity. J Biol Chem. 1989 Dec 25;264(36):21907–21914. [PubMed] [Google Scholar]
  7. Gilman A. G. G proteins and dual control of adenylate cyclase. Cell. 1984 Mar;36(3):577–579. doi: 10.1016/0092-8674(84)90336-2. [DOI] [PubMed] [Google Scholar]
  8. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  9. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol. 1987 Apr;16(4):899–906. doi: 10.1016/s0190-9622(87)80249-9. [DOI] [PubMed] [Google Scholar]
  10. Happle R. The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet. 1986 Apr;29(4):321–324. doi: 10.1111/j.1399-0004.1986.tb01261.x. [DOI] [PubMed] [Google Scholar]
  11. Higuchi M., Kochhan L., Olek K. A somatic mosaic for haemophilia A detected at the DNA level. Mol Biol Med. 1988 Feb;5(1):23–27. [PubMed] [Google Scholar]
  12. Jones D. T., Reed R. R. Molecular cloning of five GTP-binding protein cDNA species from rat olfactory neuroepithelium. J Biol Chem. 1987 Oct 15;262(29):14241–14249. [PubMed] [Google Scholar]
  13. Kuppuswamy M. N., Hoffmann J. W., Kasper C. K., Spitzer S. G., Groce S. L., Bajaj S. P. Single nucleotide primer extension to detect genetic diseases: experimental application to hemophilia B (factor IX) and cystic fibrosis genes. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1143–1147. doi: 10.1073/pnas.88.4.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Landis C. A., Masters S. B., Spada A., Pace A. M., Bourne H. R., Vallar L. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature. 1989 Aug 31;340(6236):692–696. doi: 10.1038/340692a0. [DOI] [PubMed] [Google Scholar]
  15. Levine M. A., Ahn T. G., Klupt S. F., Kaufman K. D., Smallwood P. M., Bourne H. R., Sullivan K. A., Van Dop C. Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy. Proc Natl Acad Sci U S A. 1988 Jan;85(2):617–621. doi: 10.1073/pnas.85.2.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levine M. A., Downs R. W., Jr, Moses A. M., Breslau N. A., Marx S. J., Lasker R. D., Rizzoli R. E., Aurbach G. D., Spiegel A. M. Resistance to multiple hormones in patients with pseudohypoparathyroidism. Association with deficient activity of guanine nucleotide regulatory protein. Am J Med. 1983 Apr;74(4):545–556. doi: 10.1016/0002-9343(83)91008-2. [DOI] [PubMed] [Google Scholar]
  17. Lyons J., Landis C. A., Harsh G., Vallar L., Grünewald K., Feichtinger H., Duh Q. Y., Clark O. H., Kawasaki E., Bourne H. R. Two G protein oncogenes in human endocrine tumors. Science. 1990 Aug 10;249(4969):655–659. doi: 10.1126/science.2116665. [DOI] [PubMed] [Google Scholar]
  18. Maddalena A., Sosnoski D. M., Berry G. T., Nussbaum R. L. Mosaicism for an intragenic deletion in a boy with mild ornithine transcarbamylase deficiency. N Engl J Med. 1988 Oct 13;319(15):999–1003. doi: 10.1056/NEJM198810133191507. [DOI] [PubMed] [Google Scholar]
  19. Marx S. J., Spiegel A. M., Brown E. M., Windeck R., Gardner D. G., Downs R. W., Jr, Attie M., Aurbach G. D. Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab. 1978 Dec;47(6):1190–1197. doi: 10.1210/jcem-47-6-1190. [DOI] [PubMed] [Google Scholar]
  20. Mauras N., Blizzard R. M. The McCune-Albright syndrome. Acta Endocrinol Suppl (Copenh) 1986;279:207–217. doi: 10.1530/acta.0.112s207. [DOI] [PubMed] [Google Scholar]
  21. Myers R. M., Maniatis T., Lerman L. S. Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:501–527. doi: 10.1016/0076-6879(87)55033-9. [DOI] [PubMed] [Google Scholar]
  22. Nørby S., Lestienne P., Nelson I., Rosenberg T. Mutation detection in Leber's hereditary optic neuropathy by PCR with allele-specific priming. Biochem Biophys Res Commun. 1991 Mar 15;175(2):631–636. doi: 10.1016/0006-291x(91)91612-g. [DOI] [PubMed] [Google Scholar]
  23. Patten J. L., Johns D. R., Valle D., Eil C., Gruppuso P. A., Steele G., Smallwood P. M., Levine M. A. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. N Engl J Med. 1990 May 17;322(20):1412–1419. doi: 10.1056/NEJM199005173222002. [DOI] [PubMed] [Google Scholar]
  24. Sheffield V. C., Cox D. R., Lerman L. S., Myers R. M. Attachment of a 40-base-pair G + C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes. Proc Natl Acad Sci U S A. 1989 Jan;86(1):232–236. doi: 10.1073/pnas.86.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Stork P., Loda M., Bosari S., Wiley B., Poppenhusen K., Wolfe H. Detection of K-ras mutations in pancreatic and hepatic neoplasms by non-isotopic mismatched polymerase chain reaction. Oncogene. 1991 May;6(5):857–862. [PubMed] [Google Scholar]
  26. Suarez H. G., du Villard J. A., Caillou B., Schlumberger M., Parmentier C., Monier R. gsp mutations in human thyroid tumours. Oncogene. 1991 Apr;6(4):677–679. [PubMed] [Google Scholar]
  27. Taylor S. A., Deugau K. V., Lillicrap D. P. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency). Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):39–42. doi: 10.1073/pnas.88.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Vallar L., Spada A., Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature. 1987 Dec 10;330(6148):566–568. doi: 10.1038/330566a0. [DOI] [PubMed] [Google Scholar]
  29. Weinstein L. S., Gejman P. V., Friedman E., Kadowaki T., Collins R. M., Gershon E. S., Spiegel A. M. Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8287–8290. doi: 10.1073/pnas.87.21.8287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weinstein L. S., Shenker A., Gejman P. V., Merino M. J., Friedman E., Spiegel A. M. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med. 1991 Dec 12;325(24):1688–1695. doi: 10.1056/NEJM199112123252403. [DOI] [PubMed] [Google Scholar]

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