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Science 21 August 1992:
Vol. 257. no. 5073, pp. 1118 - 1121
DOI: 10.1126/science.257.5073.1118
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Articles

Mutation of the POU-Specific Domain of Pit-1 and Hypopituitarism Without Pituitary Hypoplasia

R. W. Pfäffle 1, G. E. DiMattia 2, J. S. Parks 1, M. R. Brown 1, J. M. Wit 3, M. Jansen 3, H. Van der Nat 4, J. L. Van den Brande 3, M. G. Rosenfeld 2, and H. A. Ingraham 2

1 Division of Pediatric Endocrinology, Department of Pediatrics, Emory University School of Medicine, 2040 Ridgewood Drive, Atlanta, GA 30322
2 Howard Hughes Medical Institute, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093
3 Department of Pediatrics, University of Utrecht, Utrecht, The Netherlands
4 Laboratory for Virology, National Institutes of Public Health and Environmental Protection, Bilthoven, The Netherlands

A point mutation in the POU-specific portion of the human gene that encodes the tissuespecific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative agr helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elments but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.


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