Abstract
LUTEINIZING hormone stimulates testicular Leydig cells to produce testosterone by binding to a receptor that activates the G protein Gs and adenylyl cyclase. Testotoxicosis is a form of precocious puberty in which the Leydig cells secrete testosterone in the absence of luteinizing hormone, often due to constitutive activation of the luteinizing hormone receptor and (indirectly) Gs (refs 1–4). Here we study two unrelated boys suffering from a paradoxical combination of testotoxicosis and pseudohypoparathyroidism type la (PHP-Ia)5, a condition marked by resistance to hormones acting through cyclic AMP (parathyroid hormone and thyroid-stimulat-ing hormone) as well as a 50% decrease in erythrocyte Gs activity (the remaining 50% is due to the normal Gs allele)5,6. In both patients, a mutation in the gene encoding the Gs α-subunit replaced alanine at position 366 with serine5. We show that this αs-A366S mutation constitutively activates adenylyl cyclase in vitro, causing hormone-independent cAMP accumulation when expressed in cul-tured cells, and accounting for the testotoxicosis phenotype (as cAMP stimulates testosterone secretion). Although as-A366S is quite stable at testis temperature, it is rapidly degraded at 37 °C, explaining the PHP-Ia phenotype caused by loss of Gs activity. In vitro experiments indicate that accelerated release of GDP causes both the constitutive activity and the thermolability of αs-A366S.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Egli, C. A., Rosenthal, S. M., Grumbach, M. M., Montalvo, J. M. & Gondos, B. J. Pediat. 106, 33–40 (1984).
Reiter, E. O., Brown, R. S., Longcope, C. & Beitins, I. Z. New Engl. J. Med. 311, 515–519 (1984).
Shenker, A. et al. Nature 365, 652–654 (1993).
Spiegel, A. M., Shenker, A. & Weinstein, L. S. Endocr. Rev. 13, 536–565 (1992).
Nakomoto, J. M. et al. Clin. Res. 41, 40A (1993).
Van Dop, C. Semin. Nephrol. 9, 168–178 (1989).
Barbacid, M. A. Rev. Biochem. 56, 779–827 (1987).
Lyons, J. et al. Science 249, 655–659 (1990).
Weinstein, L. S. et al. New Engl. J. Med. 325, 1688–1695 (1991).
Graziano, M. P., Freissmuth, M. & Gilman, A. G. J. biol. Chem. 264, 409–418 (1989).
Zorgniotti, A. W. Temperature and Environmental Effects on the Testis 1–335 (Plenum, New York, 1991).
Levis, M. J. & Bourne, H. R. J. Cell Biol. 119, 1297–1307 (1992).
Bigay, J., Deterre, P., Pfister, C. & Chabre, M. FEBS Lett. 191, 181–185 (1985).
Ross, E. M. & Gilman, A. G. J. biol. Chem. 252, 6966–6969 (1977).
Katada, T., Oinuma, M. & Ui, M. J. biol. Chem. 261, 8182–8191 (1986).
Bourne, H. R., Sanders, D. A. & McCormick, F. Nature 349, 117–127 (1991).
Kaziro, Y., Itoh, H., Kozasa, T., Nakafuku, M. & Satoh, T. A. Rev. Biochem. 60, 349–400 (1991).
Noel, J. P., Hamm, H. E. & Sigler, P. B. Nature 366, 654–663 (1993).
Lambright, D. G., Noel, J. P., Hamm, H. E. & Sigler, P. B. Nature 369, 621–628 (1994).
Milburn, M. V. et al. Science 247, 939–945 (1990).
Pai, E. F. et al. EMBO J. 9, 2351–2359 (1990).
Berchtold, H. et al. Nature 365, 126–132 (1993).
Thomas, T. C., Schmidt, C. J. & Neer, E. J. Proc. natn. Acad. Sci. U.S.A. 90, 10295–10299 (1993).
Feig, L. A. & Cooper, G. M. Molec. cell. Biol. 8, 2472–2478 (1988).
Markby, D. W., Onrust, R. & Bourne, H. R. Science 262, 1895–1901 (1993).
Iiri, T., Ohaka, Y., Ui, M. & Katada, T. J. biol. Cbem. 267, 1020–1026 (1992).
Higashijima, T., Ferguson, K. M., Smigel, M. D. & Gilman, A. G. J. biol. Chem. 262, 757–761 (1987).
Masters, S. B. et al. J. biol. Chem. 264, 15467–15474 (1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Iiri, T., Herzmark, P., Nakamoto, J. et al. Rapid GDP release from Gsα in patients with gain and loss of endocrine function. Nature 371, 164–168 (1994). https://doi.org/10.1038/371164a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/371164a0
This article is cited by
-
Mapping the conformational landscape of the stimulatory heterotrimeric G protein
Nature Structural & Molecular Biology (2023)
-
A complex pheotype in a girl with a novel heterozygous missense variant (p.Ile56Phe) of the GNAS gene
Orphanet Journal of Rare Diseases (2022)
-
Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia
BMC Medical Genetics (2018)
-
Structure and dynamics of GPCR signaling complexes
Nature Structural & Molecular Biology (2018)
-
Dynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses
Nature Communications (2017)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.