MOLECULAR BASIS OF HYPOPITUITARISM IN MAN

The goal of this project is to determine the importance of pit-1 gene mutations in the development of hypopituitarism. Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Pit-1 contains two protein domains, termed POU-specific and POU-homeo, which are both necessary for high affinity DNA-binding on the growth hormone (GH) and prolactin (Prl) genes. Pit-1 is also important for hormonal regulation of the Prl and thyrotropin beta subunit (TSH-beta) genes by thyrotropin-releasing hormone (TSH-beta) and cyclic AMP (cAMP). Mutations of the pit-1 gene have been found in dwarf mouse strains displaying hypoplasia of GH, Prl, and TSH- secreting cells of the anterior pituitary, demonstrating the importance of Pit-1 for development of certain anterior pituitary cells. Many patients have also been described with complete or partial deficiency of hormone secretion from these cell types. Given these phenotypic similarities, mutations of the Pit-1 gene may be a frequent cause of anterior pituitary hormone deficiency in man. We and others have recently described a genetic basis of combined pituitary hormone deficiency (CPHD) in man due to point mutations in the Pit-1 gene. We have also discovered Pit-1 gene mutations in patients with 'idiopathic' GH deficiency associated with preserved basal Prl and TSH secretion. These observations demonstrate the importance of Pit-1 for, anterior pituitary development and function in man and indicate that mutations in the Pit-1 gene may be a frequent cause of not only CPHD, but also 'isolated' GH deficiency associated with impaired TSH and Prl responses to TRH stimulation. Major morbidity or even mortality in the neonatal and early childhood period may result when pituitary hormone deficiency is unrecognized. However a genetic basis for CPHD in man would allow for its early detection and treatment. In this study, the prevalence and characterization of hypopituitarism will be studied by evaluating hormonal responses to provocative stimuli. A major objective will then be determine how common Pit-1 gene mutations are in these patients with hypopituitarism. Equally important- functional studies of these mutations will increase the understanding of anterior pituitary gland development and gene regulation in man.