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Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination
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Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination
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Journal Article
Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination
2000
Overview
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
1
,
2
,
3
). HPE is aetiologically heterogeneous, with both environmental and genetic causes
4
,
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 cyclopia
13
. 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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animal Genetics and Genomics
/ Animals
/ Biomedical and Life Sciences
/ Chromosomes, Human, Pair 18 - genetics
/ DNA
/ DNA-Binding Proteins - metabolism
/ Gene Expression Regulation - genetics
/ Genetics
/ Holoprosencephaly - genetics
/ Homeodomain Proteins - chemistry
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ Infants
/ letter
/ Mice
/ Mutation
/ Patients
/ Prosencephalon - abnormalities
/ Proteins
/ Recombinant Fusion Proteins - chemistry
/ Recombinant Fusion Proteins - genetics
/ Recombinant Fusion Proteins - metabolism
/ Repressor Proteins - chemistry
/ Repressor Proteins - genetics
/ Repressor Proteins - metabolism
/ SHH gene
/ Trans-Activators - metabolism
