title: Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination.
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 infants). HPE is aetiologically heterogeneous, with both environmental and genetic causes. 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 cyclopia. 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-beta (TGF-beta) 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.
authors.affiliation: The Children's Hospital of Philadelphia, Departments of Pediatrics, Genetics and Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Gripp
authors.forename: D
authors.initials: D
authors.lastname: Wotton
authors.forename: M C
authors.initials: MC
authors.lastname: Edwards
authors.forename: E
authors.initials: E
authors.lastname: Roessler
authors.forename: L
authors.initials: L
authors.lastname: Ades
authors.forename: P
authors.initials: P
authors.lastname: Meinecke
authors.forename: A
authors.initials: A
authors.lastname: Richieri-Costa
authors.forename: E H
authors.initials: EH
authors.lastname: Zackai
authors.forename: J
authors.initials: J
authors.lastname: Massagué
authors.forename: M
authors.initials: M
authors.lastname: Muenke
authors.forename: S J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics*; D019556:COS Cells; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D055457:Nodal Protein; D020161:Physical Chromosome Mapping; D016548:Prosencephalon / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C097504:TGIF1 protein, human; C490797:Tgif1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D004247:DNA