A novel nonsense mutation in the Pit-1 gene: evidence for a gene dosage effect.

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 alpha-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.