The etiology of hypopituitarism is often unclear. However, several children with combined pituitary hormone deficiency (CPHD) of growth hormone (GH), prolactin (Prl), and thyrotropin were recently noted to have mutations in the pit-1 gene. Pit-1 is a member of a family of transcription factors (POU) regulating mammalian development. Expression of the pit-1 gene requires the actions of a cell-specific enhancer containing a retinoic acid response element, which needs both Pit-1 and the retinoic acid receptor (RAR) for induction by retinoic acid (RA).

Using structural and functional studies, we investigated the mechanism of CPHD in two patients with pit-1 gene mutations (R271W and K216E) present on only one allele. The R271W mutant has previously been shown to dominantly inhibit activation of the GH and Prl genes by wild type Pit-1, while the K216E mutant is a superactivator of the GH and Prl genes. We found that both of these mutant Pit-1 proteins bind to the GH and Prl genes in gel-mobility shift assays, while they are defective in their interaction with the RAR in an immunoprecipitation assay. Both mutants block RA induction via the pit-1 gene enhancer in transient transfection studies. This effect is yet another dominant negative effect of the R271W mutant. However, the K216E mutant is selectively defective in RA induction of its own gene.

Thus, CPHD can result from interruption of the interaction of a developmental factor (Pit-1) with a morphogen (RA). As the study of other mutations may help further elucidate the mechanism of hypopituitarism, we suggest DNA analysis of the pit-1 gene in patients with CPHD. Additionally, since mutations can be transmitted vertically as in the reported case of a sporadic R271W mutation, genetic analysis could also help identify neonatal hypopituitarism prior to clinical and/or biochemical abnormalities and prevent significant associated morbidity.