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The Prophet of Pit-1 gene (PROP1) encodes a paired-like homeodomain protein, which is expressed early in pituitary gland development. When mutated, it is responsible for combined pituitary hormone deficiency (CPHD) in humans, as well as in Ames dwarf mice (df/df). Several independent mutations in the homeodomain of PROP1 have been identified as causative for the human CPHD phenotype, which has been characterized, thus far, as absence or low levels of GH, PRL, TSH, LH, and FSH. Here, we report 10 CPHD cases, 9 of which were born to consanguineous marriages occurring in a large family living in an isolated area in the Southeast of Brazil. All affected patients present complete absence of puberty and low GH, PRL, TSH, LH, and FSH associated with severe hypoplasia of the pituitary gland, as seen by MRI. All 3 exons of the PROP1 genes of these patients were sequenced. The 301-302delAG frameshift mutation was found in both alleles of each affected case. Surprisingly, we observed ACTH/cortisol insufficiency associated with the PROP1 phenotype. The patients' ages varied between 8 and 67 yr, and cortisol response impairment was identified in 5 of 6 of the older patients and in an 11-yr-old patient. Previous studies have not fully characterized patients at advanced ages, leading us to conclude that the phenotype of this PROP1 mutation includes late-onset adrenal insufficiency. We present an extensive clinical analysis of all of these patients. The presence of ACTH/cortisol deficiency in this family bearing the PROP1 301-302delAG mutation indicates the importance of a complete endocrine characterization and of life-long monitoring of PROP1 patients.

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

We have analyzed the human pituitary-specific transcription factor (Pit-1) gene using PCR amplification of DNA fragments that span intron III and contain portions of exons III and IV. A PCR restriction fragment length polymorphism (PCRFLP) was detected in intron III by RsaI digestion, which was used to assign the human Pit-1 locus to chromosome 3p by linkage analysis of the CEPH panel. Analysis of corresponding Pit-1 segments from six nonrelated probands with familial panhypopituitary dwarfism (FPD) did not reveal any alterations in size and co-segregation of Pit-1, or a tightly linked microsatellite marker (D3S1559), and FPD was excluded in all six kindreds. Our data (1) assign Pit-1 to human chromosome 3p by linkage, (2) provide a PCRFLP and identify a variety of tightly linked markers, for analysis of FPD, and (3) exclude Pit-1 defects as the basis of at least one form of FPD.