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

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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.

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Figure 1: Clinical and genetic findings in five probands diagnosed with Hamamy syndrome.
Figure 2: Homeodomain IRX5 missense variants behave as hypomorphs.
Figure 3: Irx5 orchestrates migration of cranial NCCs and primordial germ cells by repressing Sdf1 expression.
Figure 4: Irx5 interacts with zinc-finger transcription factors Gata3 and Trps1 to regulate craniofacial morphogenesis.

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We are indebted to both families for agreeing to participate in this study. We thank N. Akarsu for the mapping analysis carried out on the Turkish family. We thank people from the Reversade laboratory, C.S. Chin, D. Solter and M. Escande for help and advice, and M. Seielstad for allowing genotyping experiments at the Genome Institute of Singapore. We also thank the following people for sharing materials: B. Bruneau (The Gladstone Institute), R. Morishita (Osaka University), C. Canning (Institute of Medical Biology), R.V. Thakker (University of Oxford), A. Caruz (University of Jaen) and RIKEN BioResource Center (BRC) through the National Bio-Resource Project, Japan. The authors dedicate this article to the memory of the late A.S. Teebi, a pioneer in diagnosing genetic conditions in Arab populations. This study was supported by a Singapore International Graduate Award (SINGA) fellowship to C.B., grants (108S418 and 108S420) from the Scientific and Technological Research Council of Turkey and the consortium CRANIRARE, supported by the European Research Area Network (project R07197KS). B.R. is funded by A*STAR and the Branco Weiss Foundation.

Author information

B.R. and C.B. designed the study. H.H. and H.K. diagnosed subjects. B.R., M.S., O.H.A., T.G., H.K. and H.H. collected clinical data and subject samples. C.B., B.M., H.L., S.F.N. and E.U. conducted genotyping, mapping and genomic loci capture. C.B. and A.C.S. did X. laevis work. C.B. did cell culture and biochemical studies. B.R. and C.B. wrote the manuscript.

Correspondence to Bruno Reversade.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–6 and Suppleemntary Tables 1, 3 and 4 (PDF 829 kb)

Supplementary Table 2

Sequencing workflow and list of mismatches found following loci-capturing and re-sequencing of the genomic candidate region (XLS 146 kb)

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Bonnard, C., Strobl, A., Shboul, M. et al. Mutations in IRX5 impair craniofacial development and germ cell migration via SDF1. Nat Genet 44, 709–713 (2012) doi:10.1038/ng.2259

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