GENETIC AND FUNCTIONAL ANALYSIS OF A NOVEL CONGENITAL SYNDROME AFFECTING CRANIOFACIAL DEVELOPMENT AND ONTOGENY OF MULTIPLE ORGANS

Abstract

Following homozygosity mapping and locus re-sequencing we show that homeodomain mutations in the evolutionary conserved transcription factor IRX5 cause Hamamy syndrome (HMMS); a recessive congenital disorder affecting face, eye, ear, brain, blood, heart, bone and germ cell development. We illustrate through in vivo modeling in Xenopus embryos that IRX5 modulates the migration of stem cell populations in branchial arches and gonads through the repression of Sdf1. Moreover, encompassing discrete clinical features with known human craniofacial syndromes, we demonstrate that IRX5 controls dorso-ventral eye patterning and midface expansion by direct activation of Bmp4 expression that antagonizes Shh signaling. Finally, we find that protein partners GATA3 and TRPS1 modulate IRX5 transcriptional activity of downstream genes which are essential for craniofacial development. A picture emerges whereby IRX proteins integrate combinatorial transcriptional inputs to regulate key signaling molecules involved in the ontogeny of multiple organs during embryogenesis and homeostasis.