Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified TCF7L2 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Dias et al., 2021 reported 11 individuals with de novo TCF7L2 variants presenting with a syndromic neurodevelopmental disorder; autism spectrum disorder was reported in four of these individuals.
Molecular Function
This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes (Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Tcf7l2 is a transcription factor that was identified in a forward genetic screen for ultrasonic vocalization deficits. The mutant identified in the screen exhibits vocalization deficits in pups (isolation-induced) and adults (opposite sex interaction-induced). The mutation affects the number and complexity of ultrasonic vocalizations. Passive social behavior is decreased due to lack of vocalizations. The heterozygous null mutant shows deficits in miniature post synaptic currents in the periaqueductal grey neurons. Humanized mutations found in ASD/NDD probands recapitulate vocalization deficits. There are no social or repetitive behavior deficits in the mutants studied.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The knockin deletion of exon 5' was generated using CRISPR/Cas9 technology to remove alternative exons 5'-2, 5'-3, 5'-4, 5'-5 through 5'-9.
Allele Type: Knockin
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The knockin deletion of exon 5' was generated using CRISPR/Cas9 technology to remove alternative exons 5'-2, 5'-3, 5'-4, 5'-5 through 5'-9.
Allele Type: Knockin
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The humanized knockin mutation c.932 + 1 G > A mutation alters the 5' splicing site (GT) of Tcf7l2 exon 9 to AT, potentially preventing correct splicing from exon 9 to exon 10. This mutation is identified in an ASD proband in Iossifov et al. 2014 (PMID 25363768).
Allele Type: ASD mutation
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The humanized knockin mutation c.1150 C > T (R384X) mutation introduces a premature termination codon in Tcf7l2 exon 11. This mutation is identified as a developmental delay mutation in a large-scale discovery study in Deciphering Developmental Disorders, 2015 (PMID 25533962).
Allele Type: NDD mutation
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Y337H knockin mutation was identified in an ENU-mutagenesis screen for causing impaired ultrasonic vocalizations. This non-synonymous mutation in the Tcf7l2 gene (c.T1019C, p.Y337H) is always co-segregated with USV impairment.
Allele Type: Knockin
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The knockout mutation was generated with CRISPR/Cas9 technology by introducing a two-nucleotide deletion in exon 10.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The neuronal-specific conditional knockout allele was generated by crossing a conditional ready mouse line, where exon 11 of the Tcf7l2 gene is flanked by loxP sites (MGI:5430317), with a mouse line expressing the Nestin-Cre transgenic construct (MGI:2176173).
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Richard Liu lab; Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Vglut2-specific conditional knockout allele was generated by crossing a conditional ready mouse line, where exon 11 of the Tcf7l2 gene is flanked by loxP sites (MGI:5430317), with a mouse line expressing the Vglut2-Cre transgenic construct (MGI:5141269).
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Richard Liu lab; Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Vglut2-specific conditional knockout allele was generated by crossing a conditional ready mouse line, where exon 11 of the Tcf7l2 gene is flanked by loxP sites (MGI:5430317), with a mouse line expressing the Vglut2-Cre transgenic construct (MGI:5141269).
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Richard Liu lab; Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The fx knockout allele for Tcf7l2 was generated with CRISPR/Cas9 technology, by inverting exons 9 and 10, and placing the inward-facing Lox2272:LoxP sites flanking the two inverted exons. Tcf7l2 expression can be switched on in a Cre-dependent manner. In the absence of Cre, Tcf7l2 is not expressed.
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Yichang Jia lab (PMID 36782064)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The midbrain-specific conditional knockout allele was generated by injecting a conditional ready mouse line, where exon 11 of the Tcf7l2 gene is flanked by loxP sites (MGI:5430317) with an AAV-mCherry-Cre construct at age P0. Controls were injected with an AAV-mCherry construct.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Richard Liu lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The midbrain-specific conditional knockout allele was generated by injecting a conditional ready mouse line, where exon 11 of the Tcf7l2 gene is flanked by loxP sites (MGI:5430317) with an AAV-mCherry-Cre construct at age P17. Controls were injected with an AAV-mCherry construct.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Richard Liu lab
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Vglut2-specific conditional knockin allele was generated by crossing a conditional ready mouse line, where exon 1 of the Tcf7l2 gene is flanked by loxP sites (MGI:4946910), with a mouse line expressing the Vglut2-Cre transgenic construct (MGI:5141269).
Allele Type: Conditional knockin
Strain of Origin: (129S6/SvEvTac x C57BL/6NCrl)F1
Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratories
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To generate the Aldh1l1Cre-ERT2:Tcf7l2^fl/fl strain, in which Tcf7l2 knockout is induced in astrocytes after the administration of tamoxifen (75 mg/kg body weight), Tcf7l2^tm1a/+ (MGI:4431951) animals were first crossed with flippase-expressing allele (MGI:2429412) and then with the inducible Cre recombinase-expressing allele (MGI:5806568) under the astrocyte-specific Aldh1/1 promoter.
Allele Type: Conditional knockout
Strain of Origin: C57BL/6N; 129S4/SvJaeSor; FVB/N
Genetic Background: C57BL/6NTac
ES Cell Line: JM8.N4; AK7
Mutant ES Cell Line: Model Source: Jackson laboratories
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
To determine the cell-autonomous impact of TCF7L2 on astrocyte morphology, the adeno-associated virus (AAV)-mediated delivery of CRISPR/Cas9 was used to delete Tcf7l2. On P2, AAVs were intraventricularly injected to express Cre under the astrocyte-specific gfaABC1D promoter and two guide RNAs under the U6 promoter.
Allele Type: Conditional knockout
Strain of Origin: Not applicable
Genetic Background: Not specified
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source:
Description: Mutant mice exhibited reduced expression of the short TCF7L2 form and no change in the long TCF7L2 form in the midbrain as compared to wildtype control mice.
Description: Mutant mice exhibited significantly decreased syllable number, mean frequency (kHz), peak syllable amplitude (dB), and syllable duration (ms) compared to wildtype control mice, indicating that brain-specific dnTCF7L2 is required for mouse ultrasonic vocalization production.
Description: Mutant mice exhibited absent expression of the short TCF7L2 form and no change in the long TCF7L2 form in the midbrain as compared to wildtype control mice.
Description: Mutant mice exhibited significantly decreased syllable number, mean frequency (kHz), peak syllable amplitude (dB), and syllable duration (ms) compared to wildtype control mice.
Description: Mutant mice exhibited significantly decreased syllable number, mean frequency (kHz), peak syllable amplitude (dB), and syllable duration (ms) compared to wildtype control mice.
Description: ENU-induced mutant male mice reduced both the sniffing time (s) and preference index (%) of wildtype female mice, compared to the female sniffing time and preference index in response to wildtype males.
Description: ENU-induced mutant male mice produced significantly more 'simple' syllables in the presence of a virgin female (anesthetized and awake) compared to wildtype control males.
Description: ENU-induced mutant male mice produced significantly fewer 'multiple' syllables in the presence of a virgin female (anesthetized and awake), as well as significantly fewer 'upward' syllables (awake only), compared to wildtype control virgin males.
Description: ENU-induced mutant male mice exhibited multiple ultrasonic vocalization abnormalities when in the presence of wildtype virgin females compared to wildtype controls. These include significantly fewer syllable numbers (anesthetized and awake female), lower peak amplitude (dB) (awake female only), and reduced syllable duration (ms) (anesthetized and awake female). Mutant male mice displayed no change in mean frequency (kHz) compared to wildtype control mice.
Description: ENU-induced mutant male mice exhibited impaired syllable transitions in the presence of both a anesthetized and awake female mice, compared to wildtype control male mice.
Description: Tcf7l2 heterozygous mutant male mice reduced both the sniffing time (s) and preference index (%) of wildtype female mice, compared to the female sniffing time and preference index in response to wildtype males.
Description: Tcf7l2 heterozygous mutant male mice exhibited impaired ultrasonic vocalization generation, including a significantly decreased number of syllables, reduced peak amplitude (dB), and decreased mean frequency (kHz) compared to wildtype controls.
Description: Tcf7l2 heterozygous mutant virgin male mice displayed a significantly decreased number of syllables, decreased peak syllable amplitude (dB), and lower mean frequency (kHz) with awake wildtype females compared to wildtype virgin males.
Description: Tcf7l2 heterozygous mutant mice exhibited reduced expression of high and low molecular weight TCF7L2 in the midbrain compared to wildtype controls.
Description: Tcf7l2 conditional heterozygous mutant mice displayed significantly fewer syllables, reduced peak amplitude (dB), lower mean frequency (kHz), and shorter syllable duration (ms) compared to control mice, indicating that Tcf7l2 expression in neuronal progenitors is required for ultrasonic vocalizations.
Description: Tcf7l2 conditional heterozygous mutant mice exhibited reduced expression of high and low molecular weight TCF7L2 in the midbrain compared to control mice.
Description: Mutant mice displayed significantly fewer syllables, reduced peak amplitude (dB), and shorter syllable duration (ms) compared to control mice, indicating that expression of Tcf7l2 in Vglut2-positive neurons is necessary for ultrasonic vocalizations.
Description: In the absence of Cre, mutant mice displayed significantly fewer syllables, reduced peak amplitude (dB), lower mean frequency (kHz), and shorter syllable duration (ms) compared to wildtype controls.
Description: In the absence of Cre, mutant mice exhibited reduced expression of both short and long TCF7L2 in the midbrain compared to wildtype controls.
Description: Mutant mice displayed significantly fewer syllables compared to control mice, and no change in peak syllable amplitude (dB), syllable duration (ms), or mean frequency (kHz).
Description: Mutant mice displayed significantly fewer syllables and decreased peak syllable amplitude (dB) compared to control mice. No change was present in syllable duration (ms) or mean frequency (kHz).
Description: Mutant mice displayed significantly fewer syllables, reduced peak amplitude (dB), and shorter syllable duration (ms) compared to control mice, indicating that flTCF7L2 is required for mouse ultrasonic vocalization production
Description: Mutant mice exhibited reduced expression of the long TCF7L2 form and no change in the short TCF7L2 form in the midbrain as compared to control mice.
Description: Tcf7l2 mutant mice exhibited significantly larger neighboring astrocyte overlap compared with control cells, consistent with a defect in tiling.
Description: Tcf7l2 mutant mice exhibited impairments in astrocytic gap junction function or assembly compared to controls, as measured by a reduction in the spreading of dye via gap junctions of coupled astrocytes.
Exp Paradigm: Gap junction assay
Description: Tcf7l2 exhibited a significant increase in the density of c-FOS positive neurons in response to a social scent compared to a neutral scent. While control animals exhibited a slight increase in response to a social scent compared to a neutral scent, this trend did not reach statistical significance.
Exp Paradigm: neutral scent (fresh bedding) vs. social scent (used bedding); c-FOS
Description: Tcf7l2 mutant female mice exhibited a significantly stronger preference for the social scent, spending more time in the box with the social scent compared with control mice.
Exp Paradigm: 4-box naturalistic setting; housing compartments with access to food and water in box 2 and 4, social scent in box 3 and a neutral scent in box 1
Description: Tcf7l2 mutant mice exhibited a significant increase in the ratio of the amount of time spent with the novel mouse compared to the familiar mouse in comparison to controls, suggesting an increased preference for the socially novel mouse.
Exp Paradigm: familiar mouse in chamber 1 (s1), stranger mouse (s2) in chamber 2
Description: Tcf7l2 mutant female mice exhibited a two-fold increase in sociability compared with control mice, as measured by the amount of time each pair of mice spent together throughout day 3 of the testing period.
Exp Paradigm: 4-box naturalistic setting; housing compartments with access to food and water in box 2 and 4, empty box 1 and 3; same strain, sex, and age mouse pairs
Description: Tcf7l2 mutant male and female mice spent more time around the social scent and visited the social scent area significantly more times compared to controls. No differences between mutant males and females in approach to the social scent were observed.
Exp Paradigm: social scent in chamber 1, neutral scent in chamber 2
Description: Tcf7l2 mutant mice exhibited a steady preference for the social stimulus during the entire testing period, while the preference of the control mice for the social scent decreased over the 10-min testing window.
Exp Paradigm: social scent in chamber 1, neutral scent in chamber 2
Description: RNA-seq data was validated at the protein level by quantifying the expression of astrocytic Connexins (Connexin-30 and Connexin-43), and it was observed that mutant mice exhibited a significant decrease in the number of Connexin-30 and Connexin-43 puncta compared to controls.
Exp Paradigm: Cx30
Description: Tcf7l2 mutant mice exhibited changes in the expression of 275 genes, among which 157 were downregulated and 118 were upregulated. Gene ontology analysis showed the significant enrichment of networks that are involved in glial cell differentiation, the development of gap junction, assembly, and the regulation of neuronal function.
Description: Tcf7l2 mutant mice exhibited an 85% reduction of cortical astrocytes that expressed TCF7L2 isoforms compared to controls. Tcf7l2 mutant mice exhibited similar levels to controls of TCF7L2 in other cell types in the brain, such as thalamic neurons and oligodendrocyte lineage cells.
