MUTATIONS IN PROP1 CAUSE FAMILIAL COMBINED PITUITARY-HORMONE DEFICIENCY

Combined pituitary hormone deficiency (CPHD) in man denotes impaired p roduction of growth hormone (CH) and one or more of the other five ant erior pituitary hormones. Mutations of the pituitary transcription fac tor gene POU?FI (the human homologue of mouse Pit1) are responsible fo r deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of ad renocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follic le stimulating hormone (FSH) is preserved, The Ames dwarf (df) mouse d isplays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Am es dwarf gene Prop? (ref. 1), which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is n ecessary for Pit? expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactiv ating mutations of PROP1. These mutations in the human PROP1 gene resu lt in a gene product with reduced DNA-binding and transcriptional acti vation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP? mu tations cannot produce LH and FSH at a sufficient level and do not ent er puberty spontaneously. Our results identify a major cause of CPHD i n humans and suggest a direct or indirect role for PROP? in the ontoge nesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.