McCune-Albright syndrome (MAS) is a sporadic disease characterized by café-au-lait spots, polyostotic fibrous dysplasia and hyperfunctional endocrinopathies. To elucidate the mechanism of skin pigmentation, melanocytes, keratinocytes and fibroblasts were primary cultured from the café-au-lait spot of a MAS patient. Then, mutational analysis and morphologic evaluation were performed. Also, cAMP level and tyrosinase gene expression in cultured cells were determined. Only Gsα mutation was found in affected melanocytes and the cAMP level in affected melanocytes was higher than that of normal melanocytes. The mRNA expression of tyrosinase gene was increased in the affected melanocytes. This study suggests that skin pigmentation of MAS results from activating mutation of Gsα in melanocytes and the mechanism involves the c-AMP-mediated tyrosinase gene activation.

Keywords:
McCune-Albright syndrome, G proteins, Pigmentation, Melanocytes
1.
Spiegel AM: The molecular basis of disorders caused by defects in G proteins. Horm Res 1997;47:89–96.
2.
McCune DJ: Osteitis fibrosa cystica: the case of a nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child 1936;52:743–744.
3.
Albright F, Butler AM, Hampton AO, Smith P: Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females: Report of five cases. N Engl J Med 1937;216:727–746.
4.
Weinstein LS, Shenker A, Gehman PV, Merino MJ, Friedman E, Spiegel AM: Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991;325:1688–1695.
5.
Schwindinger WF, Francomano CA, Levine MA: Identification of a mutation in the gene encoding the α subunit of the stimulatory G protein of adenyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 1992;89:5152–5156.
6.
Spiegel AM: Inborn errors of signal transduction: mutations in G proteins and G protein-coupled receptors as a cause of disease. J Inherit Metab Dis 1997;20:113–121.
7.
Happle R: The McCune-Albright syndrome: A lethal gene surviving by mosaicism. Clin Genet 1986;29:321–324.
8.
Lyons J, Landis CA, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR, McCormick F: Two G protein oncogenes in human endocrine tumors. Science 1990;249:655–659.
9.
Motomura T, Kasayama S, Takagi M, Kurebayashi S, Matsui H, Hirose T, Miyashita Y, Yamauchi-Takihara K, Yamamoto T, Okada S, Kishimoto T: Increased interleukin-6 production in mouse osteoblastic MC3T3-E1 cells expressing activating mutant of the stimulatory G protein. J Bone Miner Res 1998;3:1084–1091.
10.
Palanduz S, Cefle K, Ozturk S, Tanakol R, Tascioglu C, Koldas T, Erten NB, Karan MA: A case of McCune-Albright syndrome mimicking Paget’s disease of bone. Bone 1999;24:157–158.
11.
Kinoshita A, Greenwel P, Tanaka S, Di Liberto M, Yoshioka H, Ramirez F: A transcription activator with restricted tissue distribution regulates cell-specific expression of a1(XI) collagen. J Biol Chem 1997;272:31777–31784.
12.
Fatt PM, Price JO, Shaw A, Pietenpol JA: Differential cell cycle checkpoint response in normal human keratinocytes and fibroblasts. Cell Growth Differ 1998;9:535–543.
13.
Seitz CS, Lin Q, Deng H, Khavari PA: Alterations in NF-kB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kB. Proc Natl Acad Sci USA 1998;95:2307–2312.
14.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
15.
Shibahara S, Tomita Y, Tagami H, Muller RM, Cohen T: Molecular basis for the heterogeneity of human tyrosinase. Tohoku J Exp Med 1988;156:403–414.
16.
Ram A, Guedj F, Cravchik A, Weinstein L, Cao Q, Badner JA, Goldin LR, Grisaru Manji HK, Belmaker RH, Gershon ES, Gejman PV: No abnormality in the gene for the G protein stimulatory alpha subunit in patients with bipolar disorder. Arch Gen Psychiatry 1997;54:44–48.
17.
Rieger E, Kofler R, Borkenstein M, Schwingshandl J, Soyer HP, Kerl H: Melanotic macules following Blaschko’s lines in McCune-Albright syndrome. Br J Dermatol 1994;130:215–220.
18.
Abdel-Malek Z, Swope VB, Suzuki I, Akcali C, Harriger MD, Boyce ST, Urabe K, Hearing VJ: Mitogenic and melanogenic stimulation of normal human melanocytes by melanotropic peptides. Proc Natl Acad Sci USA 1995;92:1789–1793.
19.
Abdel-Malek Z, Swope VB, Pallas J, Krug K, Nordlund JJ: Mitogenic, melanogenic and cAMP responses of cultured neonatal human melanocytes to commonly used mitogens. J Cell Physiol 1992;150:416–425.
© 2000 S. Karger AG, Basel
2000
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.