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

Nature Genetics volume 44, pages 709–713 (2012)Cite this article

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Abstract

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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Acknowledgements

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.

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Authors and Affiliations

  1. Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Carine Bonnard, Mohammad Shboul & Bruno Reversade

  2. Division of Systems Biology, Medical Research Council National Institute for Medical Research, London, UK

    Anna C Strobl

  3. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA

    Hane Lee, Barry Merriman & Stanley F Nelson

  4. Department of Ophthalmology, Faculty of Medicine, University of Jordan, Amman, Jordan

    Osama H Ababneh

  5. Department of Biology, Faculty of Arts and Sciences, Duzce University, Duzce, Turkey

    Elif Uz

  6. Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty, Ankara, Turkey

    Elif Uz

  7. Pediatric Endocrinology and Diabetes, Marmara University Hospital, Istanbul, Turkey

    Tülay Güran

  8. Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Hülya Kayserili

  9. Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland

    Hanan Hamamy

  10. National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan

    Hanan Hamamy

  11. Department of Pediatrics, National University of Singapore, Singapore

    Bruno Reversade

Authors
  1. Carine Bonnard
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  2. Anna C Strobl
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Contributions

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.

Corresponding author

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). https://doi.org/10.1038/ng.2259

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