Molecular Mechanisms of Endocrine Disorders

  • Bruce F. Bower
  • Carl D. Malchoff
Part of the Pathology and Laboratory Medicine book series (PLM)


Molecular biologic methods and findings have had a major impact in clinical endocrinology. As a result, new concepts of hormone action have developed, major disease mechanisms have been defined, and new diagnostic strategies and therapies have been made possible. This chapter will summarize this rapidly evolving field with particular emphasis on clinical understanding and the application of molecular biologic techniques to clinical endocrine diagnosis. As a result of the pace of development, this chapter and any review will necessarily be selective, and will provide at best a window into a rapid and dynamically evolving area of clinical interest and increasing molecular understanding.


Diabetes Insipidus Medullary Thyroid Carcinoma Congenital Adrenal Hyperplasia Multiple Endocrine Neoplasia Type Williams Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rugarli, M. O. and Ballabio, A. Kallman syndrome. From genetics to neurobiology. JAMA 270:2713–2716, 1993.PubMedCrossRefGoogle Scholar
  2. 2.
    Miller, W. Editorial: molecular genetics of familial central diabetes insipidus. J. Clin. Endocrinol. Metab. 77:592–594, 1993.PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenthal, W., Seibold, A., Antaramian, A., Lonergan, M., Arthus, M. F., Hendy, G. N., Birnbaumer, M., and Bichet, D. G. Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 359:233–235, 1992.PubMedCrossRefGoogle Scholar
  4. 4.
    Cogan, J. D., Phillips, J. A., Schenkman, S. S., Milner, R. D., and Sakati, N. Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein. J. Clin. Endocrinol. Metab. 79:1261–1265, 1994.PubMedCrossRefGoogle Scholar
  5. 5.
    Haugen, B. and Ridgway, E. C. Transcription factor Pit-1 and its clinical implications: from bench to bedside. Endocrinologist 5:132–139, 1995.CrossRefGoogle Scholar
  6. 6.
    Amselem, S., Duquesnoy, P., and Goossens, M. Molecular basis of Laron’ s dwarfism. Trends Endocr. Metab. 2:35–40, 1991.CrossRefGoogle Scholar
  7. 7.
    Goddard, A. D., Covello, R. C., Louh, S., Clakson, T., Attie, K. M., Gesundheit, N., Rundle, A., Wells, J. A., and Carlsson, L. M. Mutations of the growth hormone receptor in children with idiopathic short stature. New Engl. J. Med. 333:1093–1098, 1995.Google Scholar
  8. 8.
    Merimee, T. J., Baumann, G., and Daughaday, W. H. Growth hormone binding proteins, II: studies in pygmies and normal statured subjects. J. Clin. Endocrinol. Metab. 71:1183– 1188, 1990.Google Scholar
  9. 9.
    Landis, C. A. GTPase inhibiting mutations activate the a chain of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature 340:692–696, 1989.PubMedCrossRefGoogle Scholar
  10. 10.
    Rousseau, F., Bonaventure, J., Legeai-Mallet, L., Pelet, A., Rozet, J. M., Maroteaux, P., LeMerer, M., and Munnich, A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254, 1994.PubMedCrossRefGoogle Scholar
  11. 11.
    Kopp, P., van Sande, J., Parma, J., Duprez, L., Gerber, H., Joss, E., Jameson, J. L., Dumont, J. E., Vassart, G. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. New Engl. J. Med. 331:150–154, 1995.Google Scholar
  12. 12.
    Sunthornthevarakul, T., Gottschalk, M., Hayashi, Y., and Refetoff, S. Brief report: resis-tance to thyrotropin caused by mutations in the thyrotropin-receptor gene. New Engl. J. Med. 332:155–160, 1995.Google Scholar
  13. 13.
    Usala, S. and Weintraub, B. Thyroid hormone resistance syndromes. Trends Endocr. Metab. 2:140–44, 1991.CrossRefGoogle Scholar
  14. 14.
    Refetoff, S., Weiss, R. E., and Usala, S. J. The syndromes of resistance to thyroid hor-mone. Endocr. Rev. 14:284–335, 1993.Google Scholar
  15. 15.
    Farid, N. R., Shi, Y., and Zou, M. Molecular basis of thyroid cancer. Endocr. Rev. 15:202– 232, 1994.Google Scholar
  16. 16.
    Arnold, A. Molecular genetics of parathyroid gland neoplasia. J. Clin. Endocrinol. Metab. 77:1108–1111, 1993.CrossRefGoogle Scholar
  17. 17.
    Schipani, E., Kruse, K., and Juppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268:98–100, 1995.PubMedCrossRefGoogle Scholar
  18. 18.
    Brown, E. M., Pollak, M., Seidman, C., Seidman, J. G., Chou, Y. W., Riccardi, D., and Hebert, S. C. Calcium-ion sensing cell-surface receptors. New Engl. J. Med. 333:234– 240, 1995.Google Scholar
  19. 19.
    Jalal, S. M., Crifasi, P. A., Karnes, P. S., and Michels, W. Cytogenetic testing for Will-iams syndrome. Mayo Clin. Proc. 71:67,68.Google Scholar
  20. 20.
    Driscoll, D. A., Budark, M. L., and Emanuel, B. S. A genetic etiology for Di-George syndrome: consistent deletions and microdeletions of 22q1 1. Am. J. Hum. Genet. 50:924–933, 1992.PubMedGoogle Scholar
  21. 21.
    Larson, C., Shepherd, J., Nakamura, Y., Blomberg, C., Weber, G., Werelius, B., Hayward, N., The, B., Tokino, T., Seizinger, B., Skogseid, B., Oberg, K., and Nordenskjold, M. Predictive testing for multiple endocrine n. eoplasia type 1 using DNA polymorphisms. J. Clin. Invest. 89:1344–1349, 1992.CrossRefGoogle Scholar
  22. 22.
    Levine, M. A., Vechio, J. D., and Miric, A. Heterogeneous mutations in the gene encoding the α-subunit of the stimulatory G protein of adenylyl cyclase in Albright hereditary osteodystrophy. J. Clin. Endocrinol. Metab. 76:1560–1568, 1993.CrossRefGoogle Scholar
  23. 23.
    Clapham, D. E. Signal transduction. Why testicles are cool. Nature 371:109,110, 1994.Google Scholar
  24. 24.
    Hughes, M., Malloy, P., Kieback, D., Kesterson, R. Pike, J., Feldman, D., and O’ Malley, B. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242:1702–1705, 1988.PubMedCrossRefGoogle Scholar
  25. 25.
    Weber, A., Toppari, R. D., Harvey, R. C., Klan, C., Shaw, N., Ricker, A. T., Nanto-Salonen, A. T., Vevan, J. S., and Clark, A. J. L. Adrenocorticotropin receptor gene muta-tions in familial glucocorticoid deficiency: relationships with clinical features in four families. J. Clin. Endocrinol. Metab. 80:65–71, 1995.PubMedCrossRefGoogle Scholar
  26. 26.
    Yanase, T., Simpson, E. R., and Waterman, M. R. 17α-Hydroxylase/17,20 lyase defi-ciency: from clinical investigation to molecular definition. Endocr. Rev. 12:91–104, 1992.CrossRefGoogle Scholar
  27. 27.
    Mebarki, F., Sanchez, R., Rheaume, E., Laflamme, N., Simard, J., Forest, M. G., Bey-Omar, F., David, M., Labrie, F., and Morel, Y. Nonsalt-losing male pseudo-hermaphroditism due to the novel homozygous N100S mutation in the type II 3b-hydroxysteroid dehydrogenase gene. J. Clin. Endocrinol. Metab. 80:2127–2134, 1995.CrossRefGoogle Scholar
  28. 28.
    Mercado, A. B., Wilson, R. C., Cheng, K. C., Wei, J. Q., and New, M. I. Prenatal treat-ment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 80:2014–2020, 1995.PubMedCrossRefGoogle Scholar
  29. 29.
    White, P. C., Curnow, K. M., and Pascoe, L. Disorders of steroid 1 lβ -hydroxylase isozymes. Endocr. Rev. 15: 421–438, 1994.PubMedGoogle Scholar
  30. 30.
    Malchoff, D. M., Brufsky, A., Reardon, G., McDermott, P., Javier, E. C., Bergh, C. H., Rowe, D., and Malchoff, C. D. A point mutation of the human glucocorticoid receptor in primary cortisol resistance. J. Clin. Invest. 91:1918–1925, 1993.CrossRefGoogle Scholar
  31. 31.
    Karl, M., Lamberts, S. W. J., Detera-Wadleigh, S. D., Encio, I. J., Stratakis, C. A., Hurley, D. M., Accili, D., and Chrousos, G. P. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J. Clin. Endocrinol. Metab. 76:683–689, 1993.CrossRefGoogle Scholar
  32. 32.
    Stewart, P. M., Murry, B. A., and Mason, J. I. Human kidney 1 1β-hydroxysteroid dehy-drogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type I isoform. J. Clin. Endocrinol. Metab. 79:480–484, 1994.PubMedCrossRefGoogle Scholar
  33. 33.
    Shimkets, R. A., Warnock, D. G., Bositis, C. M., Nelson-Williams, C., Hansson, J. H., Schambelan, M., Gill, J. R., Ulick, S., Milora, R. V., Findling, J. W., Canessa, C. M., Rossier, C. B., and Lifton, R. P. Liddle’ s syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell 79:407–414, 1994.PubMedCrossRefGoogle Scholar
  34. 34.
    McPhaul, M. J., Marcelli, M., Zoppi, S., Griffin, J. E., and Wilson, J. D. The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J. Clin. Endocrinol. Metab. 76:17–23, 1993.PubMedCrossRefGoogle Scholar
  35. 35.
    Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R., Lubahn, D. B., and Korach, K. S. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. New Engl. J. Med. 331:1056–1061, 1994.Google Scholar
  36. 36.
    Homaki, A. H., Dieguez Lucena, J. L., Pakarinen, P., Sistonen, P., Tapanaienen, J., Gromoll, J., Laskikari, R., Sankila, E. M., Lehvaslaiho, H., Engel, A. R., Nieschlag, E., Huhtaniemi, 1., and de La Chapelle, A. Mutation of the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959–968, 1995.CrossRefGoogle Scholar
  37. 37.
    Shenker, A., Laue, L., Kosugi, S., Merendino, J. J., Minegishi, T., and Cutler, G. B. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365:652–654, 1993.PubMedCrossRefGoogle Scholar
  38. 38.
    Jager, R. J., Anvret, M., Hall, K., and Scherer, G. A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348:352–354, 1990.CrossRefGoogle Scholar
  39. 39.
    Berta, P., Hawkins, J. R., Sinclair, A. H., Taylor, A., Griffiths, B. L., Goodfellow, P. N., and Fellous, M. Genetic evidence equating SRY and the testis-determining factor. Nature 348:448–450, 1990.PubMedCrossRefGoogle Scholar
  40. 40.
    Weinstein, L., Shenker, A., Gejman, P., Merino, M., Friedman, E., and Spiegel, A. Acti-vating mutations of the stimulatory G protein in the McCune-Albright syndrome. New Engl. J. Med. 325:1688–1695. Google Scholar
  41. 41.
    Malchoff, C. D., Reardon, G., MacGillivray, D., Yamase, H., Rogol, A. D., and Malchoff, D. M. An unusual presentation of McCune-Albright syndrome confirmed by an acti-vating mutation of the Gsa-subunit from a bone lesion. J. Clin. Endocrinol. Metab. 78:803–806, 1994.PubMedCrossRefGoogle Scholar
  42. 42.
    Goldstein, J. L. and Brown, M. S. Familial hypercholesterolemia, in The Molecular Basis ofInherited Disease, 6th ed., McGraw Hill, New York, pp. 1215–1250, 1989.Google Scholar
  43. 43.
    Brewer, H. B., Santamarina-Fojo, S., and Hoeg, J. M. Genetic defects in the human plasma apolipoproteins. Atherosclerosis Rev. 20:51–60, 1992.Google Scholar
  44. 44.
    Johns, D. R. Mitochondrial DNA and disease. New Engl. J. Med. 333:638–644, 1995.PubMedCrossRefGoogle Scholar
  45. 45.
    Frougel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., and Passa P. Familial hyperglycemia due to mutations in glucokinase New Engl. J. Med. 328:697–702, 1993.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Bruce F. Bower
  • Carl D. Malchoff

There are no affiliations available

Personalised recommendations