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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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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A novel case of global developmental delay syndrome with microdeletion at 10p14–p15.3 and microduplication at 18p11.31–p11.32
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