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Relevance to Autism

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
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior
ASD
Support
Prevalence and architecture of de novo mutations in developmental disorders
Developmental disorders
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
ID
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
ASD
DD, ID
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes
ASD
Recent Recommendation
ASD, DD, ID
Recent Recommendation
De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder
DD
ASD, ADHD, ID
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN652R001 
 splice_site_variant 
 c.1001+1G>A 
  
 De novo 
  
 Simplex 
 GEN652R002 
 splice_site_variant 
 c.685+1G>A 
  
 De novo 
  
 Simplex 
 GEN652R003 
 stop_gained 
 c.1219C>T 
 p.Arg407Ter 
 De novo 
  
 Unknown 
 GEN652R004 
 stop_gained 
 c.1804G>T 
 p.Glu602Ter 
 Familial 
 Paternal 
 Simplex 
 GEN652R005 
 intron_variant 
 c.552+49423C>T 
  
 De novo 
  
 Simplex 
 GEN652R006 
 splice_site_variant 
 c.451-1G>C 
  
 De novo 
  
  
 GEN652R007 
 missense_variant 
 c.1243C>G 
 p.Pro415Ala 
 De novo 
  
  
 GEN652R008 
 missense_variant 
 c.1319-636G>A 
  
 De novo 
  
  
 GEN652R009 
 missense_variant 
 c.1412G>T 
 p.Arg471Leu 
 Unknown 
  
  
 GEN652R010 
 missense_variant 
 c.836C>T 
 p.Pro279Leu 
 Unknown 
  
  
 GEN652R011 
 missense_variant 
 c.866C>T 
 p.Ser289Phe 
 Unknown 
  
  
 GEN652R012 
 missense_variant 
 c.971C>T 
 p.Ser324Phe 
 Unknown 
  
 Simplex 
 GEN652R013 
 missense_variant 
 c.1643C>A 
 p.Ser548Tyr 
 Unknown 
  
  
 GEN652R014 
 missense_variant 
 c.1694C>A 
 p.Ser565Tyr 
 Unknown 
  
  
 GEN652R015 
 missense_variant 
 c.1763C>T 
 p.Ser588Leu 
 Unknown 
  
  
 GEN652R016 
 missense_variant 
 c.526C>T 
 p.Arg176Trp 
 Unknown 
  
  
 GEN652R017 
 missense_variant 
 c.1211G>A 
 p.Arg404Gln 
 Unknown 
  
  
 GEN652R018 
 missense_variant 
 c.490G>A 
 p.Gly164Arg 
 Unknown 
  
  
 GEN652R019 
 missense_variant 
 c.1097C>A 
 p.Ala366Glu 
 Unknown 
  
  
 GEN652R020 
 missense_variant 
 c.1427A>G 
 p.Glu476Gly 
 De novo 
  
  
 GEN652R021 
 missense_variant 
 c.1143C>G 
 p.Asn381Lys 
 De novo 
  
  
 GEN652R022 
 missense_variant 
 c.881C>T 
 p.Pro294Leu 
 De novo 
  
  
 GEN652R023 
 stop_gained 
 c.1219C>T 
 p.Arg407Ter 
 De novo 
  
  
 GEN652R024 
 splice_site_variant 
 c.553-1G>A 
  
 De novo 
  
 Simplex 
 GEN652R025 
 stop_gained 
 c.1269T>G 
 p.Tyr423Ter 
 De novo 
  
 Simplex 
 GEN652R026 
 frameshift_variant 
 c.787del 
 p.Gln263SerfsTer22 
 De novo 
  
  
 GEN652R027 
 stop_gained 
 c.1144C>T 
 p.Gln382Ter 
 De novo 
  
  
 GEN652R028 
 frameshift_variant 
 c.660dup 
 p.Pro221ThrfsTer107 
 De novo 
  
 Simplex 
 GEN652R029 
 splice_site_variant 
 c.875+1G>C 
  
 De novo 
  
 Simplex 
 GEN652R030 
 missense_variant 
 c.1143C>G 
 p.Asn381Lys 
 De novo 
  
  
 GEN652R031 
 missense_variant 
 c.1142A>C 
 p.Asn381Thr 
 De novo 
  
 Simplex 
 GEN652R032 
 missense_variant 
 c.1250G>T 
 p.Trp417Leu 
 De novo 
  
 Simplex 
 GEN652R033 
 missense_variant 
 c.1267T>C 
 p.Tyr423His 
 De novo 
  
 Simplex 
 GEN652R034 
 missense_variant 
 c.1268A>G 
 p.Tyr423Cys 
 De novo 
  
  
 GEN652R035 
 synonymous_variant 
 c.666C>T 
 p.Ala222%3D 
 Unknown 
  
  
 GEN652R036 
 missense_variant 
 c.595C>G 
 p.Pro199Ala 
 De novo 
  
 Simplex 
 GEN652R037a 
 missense_variant 
 c.536C>A 
 p.Ser179Ter 
 Familial 
 Both parents 
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
10
Duplication
 1
 
10
Duplication
 1
 
10
Duplication
 1
 
10
Duplication
 2
 
10
Duplication
 1
 
10
Deletion
 1
 
10
Duplication
 2
 
10
Duplication
 1
 
10
Duplication
 1
 

Model Summary

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.

References

Type
Title
Author, Year
Additional
Astrocytic β-catenin signaling via TCF7L2 regulates synapse development and social behavior
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)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Targeted expression1
Abnormal
 Western blot
 P7
Ultrasonic vocalization: isolation induced1
 No change
 Monitoring ultrasonic vocalizations
 P7
 Not Reported:


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
Axin2 axin 2 29134 O70240 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
Ccnd1 cyclin D1 58919 P39948 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
CEBPA CCAAT/enhancer-binding protein zeta 12606 P53569 Luciferase reporter assay; IP
Kennell JA , et al. 2003
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
CTBP1 C-terminal binding protein 1 13016 O88712 GST; Y2H; Luciferase reporter assay
Valenta T , et al. 2003
CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 IP/WB; in vitro binding assay
Tzeng SL , et al. 2006
CTNNB1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 GST; IP/WB; ChIP; High-throughput fluorescence polarization interaction analysis assay
Del Valle-Prez B , et al. 2011
Ctnnb1 catenin (cadherin associated protein), beta 1 12387 Q02248 IP/WB
ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
Ctnnb1 catenin (cadherin-associated protein), beta 1, 88kDa 1499 Q9WU82 IP/WB
ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
DAXX death-domain associated protein 1616 Q53F85 Y2H; IP/WB; Co-localization; Luciferase reporter assay; EMSA
Tzeng SL , et al. 2006
DAZAP2 DAZ-associated protein 2 9802 Q15038 Y2H; in vitro binding assay; IP/WB; Luciferase reporter assay; ChIP
Lukas J , et al. 2009
ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R) 1994 Q15717 IP; RNP IP; IP/WB
Abdelmohsen K , et al. 2009
EP300 E1A binding protein p300 2033 Q9Y6B2 Luciferase reporter assay
Kennell JA , et al. 2003
FBLN1 fibulin 1 2192 P23142 Y2H
Wang J , et al. 2011
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
HDAC4 histone deacetylase 4 9759 P56524 GST; In vivo acetylation assay; in vitro kinase assay; AMPK kinase assay; IP/WB
Lin YY , et al. 2012
IKZF5 IKAROS family zinc finger 5 (Pegasus) 64376 Q9H5V7 IP; LC-MS/MS
Huttlin EL , et al. 2015
JUP junction plakoglobin 3728 P14923 in vitro binding assay
Miravet S , et al. 2001
Lef1 lymphoid enhancer binding factor 1 161452 Q9QXN1 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
MAD2L2 MAD2 mitotic arrest deficient-like 2 (yeast) 10459 Q9UI95 Y2H; IP/WB; Co-localization; Luciferase reporter assay
Hong CF , et al. 2009
Mbp myelin basic protein 24547 P02688 ChIP-Seq
Zhao C , et al. 2016
Myrf myelin regulatory factor 293736 D4A352 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
NLK nemo-like kinase 51701 Q9UBE8 IP/WB; EMSA
Ishitani T , et al. 2003
NR5A1 nuclear receptor subfamily 5, group A, member 1 26423 P33242 Luciferase reporter assay
Kennell JA , et al. 2003
Olig1 oligodendrocyte transcription factor 1 60394 Q9WUQ3 ChIP-Seq
Zhao C , et al. 2016
PARP1 poly (ADP-ribose) polymerase 1 142 P09874 IP; LC-MS/MS; IP/WB
Idogawa M , et al. 2007
PRMT6 protein arginine methyltransferase 6 55170 Q96LA8 IP; LC-MS/MS
Huttlin EL , et al. 2015
PSEN1 presenilin 1 5663 P49768 IP/WB
Palacino JJ , et al. 2001
PSMA3 proteasome (prosome, macropain) subunit, alpha type, 3 5684 P25788 Y2H
Wang J , et al. 2011
Sox10 SRY-box containing gene 10 20665 Q04888 IP/WB; Co-localization
Zhao C , et al. 2016
Sp5 Sp5 transcription factor 296510 A0A0G2JUC1 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
SUMO2 SMT3 suppressor of mif two 3 homolog 2 (S. cerevisiae) 6613 P61956 SILAC; TAP; LC-MS/MS
Tatham MH , et al. 2011
UBC ubiquitin C 7316 P63279 diGly proteomics
Kim W , et al. 2011
UBE2I ubiquitin-conjugating enzyme E2I (UBC9 homolog, yeast) 7329 P63279 Y2H
Wang J , et al. 2011
Ugt8 UDP glycosyltransferase 8 50555 Q09426 ChIP-Seq
Zhao C , et al. 2016
Wnt10a wingless-type MMTV integration site family, member 10A 316527 D3ZRW5 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
Wnt11 wingless-type MMTV integration site family, member 11 140584 G3V819 ChIP-Seq; ChIP-qPCR
Zhao C , et al. 2016
XRCC5 X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining) 7520 P13010 IP; LC-MS/MS; IP/WB
Idogawa M , et al. 2007
XRCC6 X-ray repair complementing defective repair in Chinese hamster cells 6 2547 P12956 IP; LC-MS/MS; IP/WB; Luciferase reporter assay
Idogawa M , et al. 2007
ZBTB33 Transcriptional regulator Kaiso 56805 Q8BN78 IP/WB
Del Valle-Prez B , et al. 2011
Zbtb33 Transcriptional regulator Kaiso 56805 Q8BN78 IP/WB; Co-localization
Zhao C , et al. 2016
Zfp24 zinc finger protein 24 360204 Q7TNK3 ChIP-Seq
Zhao C , et al. 2016

WNT11
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