A RUNX2/PEBP2 alpha A/CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Cleidocranial dysplasia (CCD), an autosomal-dominant human bone disease. is thought to be caused by heterozygous mutations in runt-related gene 2 (RUN X2)/polyomaviros enhancer binding protein 2 alpha A (PEBP2 alpha A)/core-bi nding factor A1 (CBFA1). To understand the mechanism underlying the pathoge nesis of CCD. we studied a novel mutant of RUNX2, CCD alpha A376, originall y identified in a CCD patient. The nonsense mutation, which resulted in a t runcated RUNX2 protein, severely impaired RUNX2 transactivation activity. W e show that signal transducers of transforming growth factor beta superfami ly receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance t he transactivation ability of this factor. The truncated RUNX2 protein fail ed to interact with and respond to Smads and was unable to induce the osteo blast-like phenotype in C2C12 myoblasts on stimulation by bone morphogeneti c protein. Therefore, the pathogenesis of CCD may be related to the impaire d Smad signaling of transforming growth factor beta/bone morphogenetic prot ein pathways that target the activity of RUNX2 during bone formation.