HUMAN PROP-1 - CLONING, MAPPING, GENOMIC STRUCTURE - MUTATIONS IN FAMILIAL COMBINED PITUITARY-HORMONE DEFICIENCY

Prop-1 is a newly isolated pituitary-specific paired-like homeodomain transcription factor whose cDNA sequence is well known in mouse. To st udy its involvement in human combined pituitary hormone deficiency (CP HD), we have isolated the human cDNA ortholog and determined the exon/ intron organization and chromosomal localization of the human gene. A Prop-1 defect was characterized in three CPHD families. One missense m utation (R73C) involves a residue conserved in 95% of the more than 40 0 homeodomain proteins so far identified; in vitro splicing assays dem onstrated the functional importance of the second defect, whereas the remaining mutation is a frameshift, Given the disease phenotype docume nted in the patients, these data, which will facilitate molecular inve stigations in other patients, demonstrate the crucial role of Prop-1 i n the proper development of somatotrophs, lactotrophs, thyreotrophs an d gonadotrophs. (C) 1998 Federation of European Biochemical Societies.