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.

Expression and functional analysis of Tgif during mouse midline development

“…Our result is consistent with a recent report by Shen and Walsh (2005). This result is strikingly different from the human study, which revealed that loss of Tgif function is associated with human HPE, a typical ventral forebrain malformation (Gripp et al, 2000). This discrepancy suggests that additional genetic insults may also contribute to the HPE phenotype associated with patients bearing Tgif mutations, whereas the loss of TGIF function in mice may be compensated for by other TGF-␤ antagonists.…”

“…The human TGIF gene is mapped to 18p11.3, a critical region for HPE (Gripp et al, 2000). Mutations of TGIF have been found in various HPE patients.…”

“…For example, mutations in the N-terminal repression domain were detected in patients with mild HPE symptoms such as hypotelorism, whereas mutations in the homeodomain, Smad, and HDAC interacting domains were responsible for more severe symptoms such as lobar and semilobar HPEs (Gripp et al, 2000). Interestingly, all the mutant forms of TGIF, except for the one with a mutated homeodomain, retain DNA binding ability (Gripp et al, 2000). These data suggest that TGIF is a candidate gene for HPE and that TGIF function is required for ventral forebrain specification (Gripp et al, 2000).…”

“…Interestingly, all the mutant forms of TGIF, except for the one with a mutated homeodomain, retain DNA binding ability (Gripp et al, 2000). These data suggest that TGIF is a candidate gene for HPE and that TGIF function is required for ventral forebrain specification (Gripp et al, 2000). However, a number of studies have demonstrated that Smad2-mediated TGF-␤ signaling in the axial mesendoderm is essential for the specification of ventral forebrain.…”

TGIF, a gene associated with human brain defects, regulates neuronal development

“…HPE is etiologically heterogeneous, and a number of both environmental and genetic causes have been identified (Muenke and Beachy, 2000;Ming and Muenke, 2002). Mutations in seven genes have been noted to cause human HPE: SHH (Roessler et al, 1996(Roessler et al, , 1997, ZIC2 (Brown et al, 1998), SIX3 (Wallis et al, 1999), TGIF (Gripp et al, 2000), PTCH (Ming et al, 2002b), TDGF1 (De La Cruz et al, 2002), and GLI2 (Roessler et al, 2003). Several other candidate genes for HPE also exist (Kamnasaran et al, 2005).…”