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A Novel Nonsense Mutation in the Pit-1 Gene: Evidence for a Gene Dosage Effect

Division of Endocrinology, Children’s Hospital and Harvard Medical School (Y.H., L.E.C.), Boston, Massachusetts 02115; and Department of Pediatrics, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, University of Pavia (M.C.), 27100 Pavia, Italy

Address all correspondence and requests for reprints to: Laurie E. Cohen, M.D., Children’s Hospital, Division of Endocrinology, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: laurie.cohen{at}tch harvard.edu.

The POU transcription factor Pit-1 functions in the development of somatotrophs, lactotrophs, and thyrotrophs of the anterior pituitary gland. It also plays a role in cell-specific gene expression and regulation of the gene products from these cell types, GH, prolactin, and TSH, respectively. In the present report we studied a patient with severe growth failure. Provocative studies revealed undetectable GH, prolactin, and TSH levels, and her pituitary gland was hypoplastic on magnetic resonance imaging. She had a novel homozygous nonsense mutation in the 3' end of the first -helix of the POU-specific domain of the Pit-1 gene. This mutation results in a truncated protein with loss of most of the Pit-1 DNA-binding domains. Interestingly, her parents, who each have one mutant allele, have evidence of mild endocrine dysfunction. Thus, two normal copies of the Pit-1 gene appear necessary for full Pit-1 gene function.

This work was supported in part by NIH Grant K11-DK-02329 from the National Institute of Diabetes and Digestive and Kidney Diseases (to L.E.C.) and by the Genentech Foundation for Growth and Development (to L.E.C.).

Present address for Y.H.: Department of Neurology, Gunma University School of Medicine, Maebashi, 371-8711 Gunma, Japan.

Abbreviations: CPHD, Combined pituitary hormone deficiency; e, embryonic day; EV, empty vector; h, human; MRI, magnetic resonance imaging; POU-H, POU-homeo; POU-S, POU-specific; PRL, prolactin.