Nature Genetics
25, 205 - 208 (2000)
doi:10.1038/76074
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determinationKaren W. Gripp1, David Wotton2, 9, Michael C. Edwards3, 4, 9, Erich Roessler5, Lesley Ades6, Peter Meinecke7, Antonio Richieri-Costa8, Elaine H. Zackai1, Joan Massagué2, Maximilian Muenke1, 5
& Stephen J. Elledge3, 41
The Children's Hospital of Philadelphia, Departments of Pediatrics, Genetics and Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 2
Cell Biology Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 3
Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA. 4
Department of Molecular and Human Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 5
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 6
Royal Alexandra Hospital for Children, Parramatta, Australia. 7
Altonauer Kinderkrankenhaus, Hamburg, Germany. 8
University of Sao Paulo, Bauru, Sao Paulo, Brazil. 9
These authors contributed equally to this work.
Correspondence should be addressed to Maximilian Muenke mmuenke@nhgri.nih.govHoloprosencephaly (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- (TGF-) 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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