Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1.

TitleMutations in IRX5 impair craniofacial development and germ cell migration via SDF1.
Publication TypeJournal Article
Year of Publication2012
AuthorsBonnard, C, Strobl AC, Shboul M, Lee H, Merriman B, Nelson SF, Ababneh OH, Uz E, G├╝ran T, Kayserili H, Hamamy H, Reversade B
JournalNature genetics
Date Published2012 Jun
KeywordsAbnormalities, Multiple, Animals, Base Sequence, Bone and Bones, Brain, Branchial Region, Craniofacial Abnormalities, DNA-Binding Proteins, Female, GATA3 Transcription Factor, Gene Expression Regulation, Gonads, Heart Defects, Congenital, Homeodomain Proteins, Humans, Male, Molecular Sequence Data, Pedigree, Syndrome, Transcription Factors, Xenopus laevis, Xenopus Proteins

Using homozygosity mapping and locus resequencing, we found that alterations in the homeodomain of the IRX5 transcription factor cause a recessive congenital disorder affecting face, brain, blood, heart, bone and gonad development. We found through in vivo modeling in Xenopus laevis embryos that Irx5 modulates the migration of progenitor cell populations in branchial arches and gonads by repressing Sdf1. We further found that transcriptional control by Irx5 is modulated by direct protein-protein interaction with two GATA zinc-finger proteins, GATA3 and TRPS1; disruptions of these proteins also cause craniofacial dysmorphisms. Our findings suggest that IRX proteins integrate combinatorial transcriptional inputs to regulate key signaling molecules involved in the ontogeny of multiple organs during embryogenesis and homeostasis.

Alternate JournalNat. Genet.