Mutations in PROP1 cause familial combined pituitary hormone deficiency (original) (raw)

Nature Genetics volume 18, pages 147–149 (1998)Cite this article

Abstract

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteiniz-ing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1 (ref. 1)f which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report we have identified four CPHD families with homozy-gosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Sornson, M.W. et al Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism Nature 384, 327–333 (1996).
    Article CAS Google Scholar
  2. Raskin, S. et al. Genetic mapping of the human pituitary-specific transcriptional factor gene and its analysis in familial panhypopituitary dwarfism. Hum. Genet. 98, 703–705 (1996).
    Article CAS Google Scholar
  3. Bartke, A. The response of two types of dwarf mice to growth hormone, thyrotropin, and thyroxine. Gen. Comp. Endocrinol. 5, 418–426 (1965).
    Article CAS Google Scholar
  4. Bartke, A. Genetic models in the study of anterior pituitary hormones, in Genetic Variation in hormone system (ed. Shire, J.) 111-126 (CRC Press, Boca Raton, 1979).
    Google Scholar
  5. Buckwalter, M.S., Katz, R.W. & Camper, S.A. Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in an intersubspecific backcross. Genomics 10, 515–526 (1991).
    Article CAS Google Scholar
  6. Gage, P.J., Lossie, A.C., Scarlett, L.M., Lloyd, R.V. & Camper, S.A. Ames dwarf mice exhibit somatotrope commitment but lack growth hormone- releasing factor response. Endocrinology 136, 1161–1167 (1995).
    Article CAS Google Scholar
  7. Gage, P.J., Roller, M.L., Saunders, T.L., Scarlett, L.M. & Camper, S.A. Anterior pituitary cells defective in the cell-autonomous factor, df, undergo cell lineage specification but not expansion. Development 122, 151–160 (1996).
    CAS Google Scholar
  8. Kappen, C., Schughart, K. & Ruddle, F.H. Early evolutionary origin of major homeodomain sequence classes. Genomics 18, 54–70 (1993).
    Article CAS Google Scholar
  9. Andersen, B. et al. The Ames dwarf gene is required for Pit-1 gene activation. Dev. Biol. 172, 495–503 (1995).
    Article CAS Google Scholar
  10. Tang, K., Bartke, A., Gardiner, C.S., Wagner, T.E. & Yun, J.S. Gonadotropin secretion, synthesis, and gene expression in human growth hormone transgenic mice and in Ames dwarf mice. Endocrinology 132, 2518–2524 (1993).
    Article CAS Google Scholar
  11. Pf¨affle, R.W. et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257, 1118–1121 (1992).
    Article Google Scholar
  12. Cohen, L.E. et al. A ”hot spot“ in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates. J. Clin. Endocrinol. Metab. 80, 679–684 (1995).
    CAS PubMed Google Scholar
  13. Tatsumi, K. et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nature Genet. 1, 56–58 (1992).
    Article CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, University of California at San Diego, Lajolla, California, 92093-0648, USA
    Wei Wu, Jeremy S. Dasen, Shawn M. O'Connell, Sarah E. Flynn & Michael G. Rosenfeld
  2. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, 37232, USA
    Joy D. Cogan & John A. Phillips III
  3. Department of Pediatrics, RWTH Aachen School of Medicine, 52057, Aachen, Germany
    Roland W. Pfäffle
  4. Division of Endocrinology, Department of Pediatrics, University of Vienna, 1090, Wien, Austria
    Herwig Frisch
  5. Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, 30322, USA
    Milton R. Brown & John S. Parks
  6. Division of Endocrinology, Department of Pediatrics, University of Bern, Inselspital, CH-3010, Bern, Switzerland
    Primus E. Mullis

Authors

  1. Wei Wu
    You can also search for this author inPubMed Google Scholar
  2. Joy D. Cogan
    You can also search for this author inPubMed Google Scholar
  3. Roland W. Pfäffle
    You can also search for this author inPubMed Google Scholar
  4. Jeremy S. Dasen
    You can also search for this author inPubMed Google Scholar
  5. Herwig Frisch
    You can also search for this author inPubMed Google Scholar
  6. Shawn M. O'Connell
    You can also search for this author inPubMed Google Scholar
  7. Sarah E. Flynn
    You can also search for this author inPubMed Google Scholar
  8. Milton R. Brown
    You can also search for this author inPubMed Google Scholar
  9. Primus E. Mullis
    You can also search for this author inPubMed Google Scholar
  10. John S. Parks
    You can also search for this author inPubMed Google Scholar
  11. John A. Phillips III
    You can also search for this author inPubMed Google Scholar
  12. Michael G. Rosenfeld
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Wu, W., Cogan, J., Pfäffle, R. et al. Mutations in _PROP_1 cause familial combined pituitary hormone deficiency.Nat Genet 18, 147–149 (1998). https://doi.org/10.1038/ng0298-147

Download citation