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

Nat Genet. 2012 May 13;44(6):709-13. doi: 10.1038/ng.2259.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Animals
  • Base Sequence
  • Bone and Bones / abnormalities
  • Brain / abnormalities
  • Branchial Region / cytology
  • Craniofacial Abnormalities / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • GATA3 Transcription Factor
  • Gene Expression Regulation
  • Gonads
  • Heart Defects, Congenital / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Repressor Proteins
  • Syndrome
  • Transcription Factors / genetics*
  • Xenopus Proteins
  • Xenopus laevis / genetics


  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • GATA3 protein, Xenopus
  • Homeodomain Proteins
  • IRX5 protein, human
  • Repressor Proteins
  • TRPS1 protein, human
  • Transcription Factors
  • Xenopus Proteins