Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination (original) (raw)

Nature Genetics volume 25, pages 205–208 (2000)Cite this article

Abstract

Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants1,2,3). HPE is aetiologically heterogeneous, with both environmental and genetic causes4,5. So far, three human HPE genes are known: SHH at chromosome region 7q36 (ref. 6); ZIC2 at 13q32 (ref. 7); and SIX3 at 2p21 (ref. 8). In animal models, genes in the Nodal signalling pathway, such as those mutated in the zebrafish mutants cyclops (refs 9,10), squint (ref. 11) and one-eyed pinhead (oep; ref. 12), cause HPE. Mice heterozygous for null alleles of both Nodal and Smad2 have cyclopia13. Here we describe the involvement of the TG-interacting factor (TGIF), a homeodomain protein, in human HPE. We mapped TGIF to the HPE minimal critical region in 18p11.3. Heterozygous mutations in individuals with HPE affect the transcriptional repression domain of TGIF, the DNA-binding domain or the domain that interacts with SMAD2. (The latter is an effector in the signalling pathway of the neural axis developmental factor NODAL, a member of the transforming growth factor-β (TGF-β) family.) Several of these mutations cause a loss of TGIF function. Thus, TGIF links the NODAL signalling pathway to the bifurcation of the human forebrain and the establishment of ventral midline structures.

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Acknowledgements

We thank the patients and their families for participation; D. Mowat for clinical information; and K. Mahon and P. Beachy for discussions. K.W.G. was supported by the Howard Hughes Medical Institute. M.C.E. was supported by a Cellular and Molecular Biology of Aging Training Grant. This work was supported by NIH grants to M.M., J.M. and S.J.E.; by an NIH grant to the Memorial Sloan-Kettering Cancer Center; and by the Division of Intramural Research, National Human Genome Research Institute, NIH to M.M. S.J.E. and J.M. are Investigators with the Howard Hughes Medical Institute.

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Author notes

  1. David Wotton and Michael C. Edwards: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pediatrics, The Children's Hospital of Philadelphia, Genetics and Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Karen W. Gripp, Elaine H. Zackai & Maximilian Muenke
  2. Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
    David Wotton & Joan Massagué
  3. Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA
    Michael C. Edwards & Stephen J. Elledge
  4. Department of Molecular and Human Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
    Michael C. Edwards & Stephen J. Elledge
  5. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
    Erich Roessler & Maximilian Muenke
  6. Royal Alexandra Hospital for Children, Parramatta, Australia
    Lesley Ades
  7. Altonauer Kinderkrankenhaus, Hamburg, Germany
    Peter Meinecke
  8. University of Sao Paulo, Bauru, Sao Paulo, Brazil
    Antonio Richieri-Costa

Authors

  1. Karen W. Gripp
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  2. David Wotton
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  3. Michael C. Edwards
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  4. Erich Roessler
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  5. Lesley Ades
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  6. Peter Meinecke
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  7. Antonio Richieri-Costa
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  8. Elaine H. Zackai
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  9. Joan Massagué
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  10. Maximilian Muenke
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  11. Stephen J. Elledge
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Corresponding author

Correspondence toMaximilian Muenke.

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Gripp, K., Wotton, D., Edwards, M. et al. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination.Nat Genet 25, 205–208 (2000). https://doi.org/10.1038/76074

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