THE HUMAN BONE MORPHOGENETIC PROTEIN-4 (BMP-4) GENE - MOLECULAR-STRUCTURE AND TRANSCRIPTIONAL REGULATION

Bone morphogenetic protein 4 (BMP-4) is a vital regulatory molecule th at functions throughout human development in mesoderm induction, tooth development, limb formation, bone induction, and fracture repair and is overexpressed in patients who have fibrodysplasia ossificans progre ssiva. The human gene encoding bone morphogenetic protein 4 (BMP-4) ha s been isolated and its structural organization characterized. The com plete DNA sequence of an 11.2 kb region has been determined. BMP-4 mRN A is transcribed from four exons, although there is evidence that alte rnate first exons may be used. Transcript initiation occurs at variabl e positions within a GA-rich region of the DNA, The promoter region is CC-rich with no obvious TATA or CAAT consensus sequences, and contain s both positive and negative transcriptional regulatory elements withi n the 3 kb 5' flanking region of the RNA start site. Comparison of the human and murine BMP-4 genes reveals highly conserved sequences not o nly in the exon-coding regions but also within the introns and 5' flan king regions. BMP-4 localizes to human chromosome 14q21 by fluorescenc e in situ hybridization, a location more centromeric than that recentl y reported. These studies provide a foundation for understanding the g enetic regulation of this important gene in human development.