Mutations in PROP1 cause familial combined pituitary hormone deficiency

• Published in: Nature genetics Vol. 18; no. 2; pp. 147 - 149
• Main Authors: WEI WU, COGAN, J. D, PHILLIPS, J. A, ROSENFELD, M. G, PFÄFFLE, R. W, DASEN, J. S, FRISCH, H, O'CONNELL, S. M, FLYNN, S. E, BROWN, M. R, MULLIS, P. E, PARKS, J. S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-02-1998
• Subjects: Adolescent; Adult; Amino Acid Sequence; Animals; Biological and medical sciences; Carrier Proteins - genetics; Child; Conserved Sequence; Dwarfism - genetics; Endocrinopathies; Female; Growth Hormone - deficiency; Heterozygote; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - chemistry; Homeodomain Proteins - genetics; Homozygote; Human Growth Hormone - deficiency; Humans; Hypopituitarism - genetics; Hypothalamus. Hypophysis. Epiphysis (diseases); Male; Medical sciences; Membrane Proteins; Mice; Mice, Mutant Strains; Molecular Sequence Data; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pedigree; Phospholipid Transfer Proteins; Pituitary Hormones - deficiency; Prolactin - deficiency; Saccharomyces cerevisiae Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Thyrotropin - deficiency; Transcription Factors - biosynthesis; Transcription Factors - chemistry; Transcription Factors - genetics; Endocrinopathy; Human; Embryonic development; Nucleotide sequence; Deficiency; STH; Homology; Gene expression; Genetic disease; Protein hormone; Pituitary hormone; Adenohypophyseal hormone; Pituitary diseases; Homeotic gene; Genetics; Mutation; Transcription factor
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng0298-147

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.