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Relevance to Autism

A number of de novo variants, including three de novo loss-of-function (LoF) variants, have been identified in ASD probands from the MSSNG cohort, the Autism Sequencing Consortium, the SPARK cohort, and the Simons Simplex Collection (Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022). Transmission and de novo association (TADA) analysis of whole-exome and whole-genome sequencing data from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Trost et al., 2022 identified TSHZ1 as an ASD-associated gene with a false discovery rate (FDR) < 0.1.

Molecular Function

This gene encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. The encoded protein is a member of the teashirt C2H2-type zinc-finger protein family and may be involved in transcriptional regulation of developmental processes. Mutations in this gene are associated with congenital aural atresia (OMIM 607842), an autosomal dominant syndrome characterized by conductive hearing impairment, atresia of the external auditory canal, and hyposmia (Feenstra et al., 2011).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans
Congenital aural atresia
Support
Integrating de novo and inherited variants in 42
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Recent Recommendation
Genomic architecture of autism from comprehensive whole-genome sequence annotation
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1370R001a 
 frameshift_variant 
 c.410del 
 p.Lys137ArgfsTer125 
 De novo 
  
 Multiplex 
 GEN1370R001b 
 missense_variant 
 c.409A>C 
 p.Lys137Gln 
 De novo 
  
 Multiplex 
 GEN1370R002 
 frameshift_variant 
 c.468_469insCCCCCCCCCCCCCCCC 
 p.Thr157ProfsTer68 
 De novo 
  
  
 GEN1370R003 
 missense_variant 
 c.592G>A 
 p.Asp198Asn 
 De novo 
  
  
 GEN1370R004 
 synonymous_variant 
 c.2301G>A 
 p.Ser767%3D 
 De novo 
  
 Simplex 
 GEN1370R005 
 synonymous_variant 
 c.1626C>T 
 p.Asp542%3D 
 De novo 
  
  
 GEN1370R006 
 frameshift_variant 
 c.853del 
 p.Arg285GlyfsTer10 
 De novo 
  
  
 GEN1370R007 
 synonymous_variant 
 c.798C>T 
 p.Asn266%3D 
 De novo 
  
  
 GEN1370R008 
 synonymous_variant 
 c.1905C>T 
 p.Asn635= 
 De novo 
  
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
18
Duplication
 2
 
18
Duplication
 2
 
18
Duplication
 2
 
18
Deletion
 6
 
18
Deletion
 6
 
18
Deletion
 9
 
18
Deletion-Duplication
 5
 
18
Deletion-Duplication
 8
 
18
Deletion
 4
 
18
Deletion
 1
 
18
Deletion-Duplication
 19
 
18
Deletion-Duplication
 8
 
18
Deletion
 1
 

Model Summary

Tshz1 null mutations result in a stark decrease in the number of intercalated interneurons in the lateral paracapsular clusters and the intercalated nucleus of the amygdala. Mutant mice show deficits in neuronal differentiation and an increase in apoptosis. Behaviorally,, mutant mice show decreased exploratory behavior and increased depression-like behavior. Mutant mice also show decreased social behaviors, such as decreased social approach, decreased social interaction, decreased aggression and increased social withdrawal.

References

Type
Title
Author, Year
Model Type: Genetic
Model Genotype: Compound heterozygous
Mutation: The germline knockout is a compound heterozygote, with one allele being a substitution of most of the Tshz1 gene with a gene for GFP in the Tshz1 locus, resulting in a fusion protein of the first 18 amino acids of Tshz1 and GFP (Tshz1^GFP, MGI:5588813). The other allele is a germline deletion of Tshz1 created by using a floxed, conditional ready allele (Tshz1^flox, MGI:5588816), where exon 2 is excised in the germline after crossing with a transgenic mouse carrying EIIA-Cre (MGI:2137691). After germline deletion, the Cre transgene was crossed out, and the resulting allele was a constitutive germline deletion (Tshz1^RA). The genotype of this mutant is Tshz1^GFP/RA, and controls used are heterozygotes Tshz1^GFP/+.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd; (129X1/SvJ x 129S1/Sv)F1-Kitl+; FVB/
Genetic Background: Outbred
ES Cell Line: E14.1; R1
Mutant ES Cell Line:
Model Source: Alistair Garratt lab (PMID 24487590); Jackson Laboratory (RRID: IMSR_JAX:003724)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal specification1
Abnormal
 In situ hybridization (ISH)
 E16.5
Neuronal number: interneurons1
Decreased
 Fluorescence microscopy
 E18.5
Neuronal differentiation1
Decreased
 Fluorescence microscopy
 E18.5
Gene expression1
Increased
 In situ hybridization (ISH)
 E16.5
Gene expression1
Decreased
 Fluorescence microscopy
 E16.5
Differential gene expression1
Abnormal
 RNA sequencing
 E16.5
 Not Reported:

 

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