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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

Rare

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 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
18
Duplication
 2
 
18
Duplication
 2
 
18
Duplication
 2
 
18
Deletion
 5
 
18
Deletion
 4
 
18
Deletion
 8
 
18
Deletion-Duplication
 5
 
18
Deletion-Duplication
 8
 
18
Deletion
 3
 
18
Deletion
 1
 
18
Deletion-Duplication
 18
 
18
Deletion-Duplication
 5
 
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

M_TSHZ1_1_KO

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)

M_TSHZ1_2_CKO

Model Type: Genetic
Model Genotype: Compound heterozygous
Mutation: The ventral forebrain-specific conditional 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 ventral forebrain-specific deletion of Tshz1 created by using a floxed, conditional ready allele (Tshz1^flox, MGI:5588816), where exon 2 is excised in the ventral forebrain after crossing with a transgenic mouse carrying Dlx1-Cre (MGI: 5086204). The genotype for this mutant is Tshz1^GFP/flox; Dlx1-Cre, and the controls used are heterozygotes Tshz1^GFP/+, Dlx1-Cre.
Allele Type: Conditional 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); GENSAT (RRID:MMRRC_036076-UCD)

M_TSHZ1_3_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: The ventral forebrain-specific conditional knockout is a homozygote, with both alleles in the Tshz1 locus having a ventral forebrain-specific deletion of Tshz1 created by using a floxed, conditional ready allele (Tshz1^flox, MGI:5588816), where exon 2 is excised in the ventral forebrain after crossing with a transgenic mouse carrying Dlx1-Cre (MGI:5086204). The genotype for this mutant is Tshz1^flox/flox; Dlx1-Cre, and the controls used are conditional heterozygotes Tshz1^flox/+; Dlx1-Cre.
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+; FVB/Ntac
Genetic Background: Outbred
ES Cell Line: R1
Mutant ES Cell Line:
Model Source: Alistair Garratt lab (PMID 24487590); GENSAT (RRID:MMRRC_036076-UCD)

M_TSHZ1_1_KO

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal number: interneurons1
Decreased
Description: Tshz1 mutant mice exhibited an 82.9% reduction in the number of intercalated cells in the lateral paracapsular clusters and an 82.2% reduction in the number of intercalated cells in the intercalated nucleus of the amygdala compared to control mice. No differences were observed in the number of intercalated cells in the medial paracapsular clusters between mutant and control mice.
Exp Paradigm: GFP, Er81, Mef2c
 Fluorescence microscopy
 E18.5
Neuronal differentiation1
Decreased
Description: Tshz1 mutant mice exhibited aberrant expression of Sp8 and Foxp2. Mutant mice displayed increased numbers of Sp8-positive neuronal progenitors compared to control mice, with averages of 57.7% and 8.4%, respectively. Mutant mice displayed decreased numbers of Foxp2-positive mature neurons compared to control mice, with averages of 62.4% and 95.0%, respectively.
Exp Paradigm: GFP, Sp8, Foxp2
 Fluorescence microscopy
 E18.5
Neuronal specification1
Abnormal
Description: Tshz1 mutant mice exhibited ectopic Adora2a (adenosine receptor that marks the indirect pathway in the striatum of wildtype mice) expression in intercalated cells compared to controls.
Exp Paradigm: Adora2a
 In situ hybridization (ISH)
 E16.5
Gene expression1
Decreased
Description: Immunostaining of Tshz1 mutants confirmed a reduction of ErbB4 compared to control mice.
Exp Paradigm: GFP, Erbb4
 Fluorescence microscopy
 E16.5
Differential gene expression1
Abnormal
Description: According to gene-expression profiling of the caudal ventral telencephalon, Tshz1 mutant mice exhibited the upregulation of 131 genes and downregulation of 85 genes, compared to control mice. Downregulated genes include ErbB4, Prokr2, and Dcc.
Exp Paradigm: Flow cytometric sorting of GFP-positive cells
 RNA sequencing
 E16.5
Gene expression1
Increased
Description: Tshz1 mutant mice exhibited robust upregulation of Cyp26b1 in intercalated cells.
Exp Paradigm: Cyp26b1
 In situ hybridization (ISH)
 E16.5
 Not Reported:

M_TSHZ1_2_CKO

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal number: interneurons1
Decreased
Description: Tshz1 mutant mice exhibited an 83.4% reduction in the number of intercalated cells in the lateral paracapsular clusters, an 84.1% reduction in the number of intercalated cells in the intercalated nucleus of the amygdala, and a 53% reduction in the number of intercalated cells in the medial paracapsular clusters, compared to control mice.
Exp Paradigm: GFP, Tshz1
 In situ hybridization (ISH)
 P3
Neuronal differentiation1
Decreased
Description: Tshz1 mutant mice exhibited aberrant expression of Sp8 and Foxp2. Mutant mice displayed increased numbers of Sp8-positive neuronal progenitors compared to control mice, with averages of 32.1% and 2.4%, respectively. Mutant mice displayed decreased numbers of Foxp2-positive mature neurons compared to control mice, with averages of 60.3% and 90.5%, respectively.
Exp Paradigm: GFP, Sp8, Foxp2
 Fluorescence microscopy
 P3
Neuronal specification1
Abnormal
Description: Tshz1 mutant mice exhibited an increased number of Foxp1-positive striatal projection neurons compared to control mice, with 19.8% and 0.0003% coexpression, respectively.
Exp Paradigm: GFP, Foxp1
 Fluorescence microscopy
 P3
Neuronal number: interneurons1
Decreased
Description: Tshz1 mutant mice exhibited an 89.8% reduction in the number of intercalated cells in the lateral paracapsular clusters, a 70.4% reduction in the number of intercalated cells in the intercalated nucleus of the amygdala, and a 46.7% reduction in the number of intercalated cells in the medial paracapsular clusters, compared to control mice.
Exp Paradigm: GFP, Er81, Mef2c
 Fluorescence microscopy
 P21
Neuronal apoptosis1
Increased
Description: Tshz1 mutant mice exhibited an increase in the number of apoptotic intercalated cells compared to control mice, as measured by cleaved Caspase-3 labeling. Within the lateral migratory stream and amygdala of mutant animals there was a 1.3-fold increase in cleaved Caspase-3-positive cells compared with controls.
Exp Paradigm: GFP, cleaved caspase 3
 Fluorescence microscopy
 P0.5
 Not Reported:

M_TSHZ1_3_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
Description: Tshz1 mutant mice were 1.30 times as active as control mice, as measured by total distance traveled.
 Open field test
 6-7 months
Social interaction1
Decreased
Description: Tshz1 mutant mice spent a significantly shorter portion of the trial engaging in active social behaviors with the partner mouse, regardless of the partnerâ??s genotype (67.6% reduction for control partners; 83.5% reduction for mutant partners), compared to control mice. Both control and mutant behavior patterns were highly dependent on the genotype of the partner mouse. Control mice, for example, spent 95.0% more time engaging in active social behavior with mutant partners than with control partners.
 Reciprocal social interaction test
 6-7 months
Social dominance1
Decreased
Description: Tshz1 mutant mice paired with control partners displayed a 3.33-fold increase in the number of passive behaviors (freezing, fleeing, defensive posturing, or defeat posturing) compared with mutant partners. This was significantly greater than the number of passive behaviors displayed by a control mouse paired with a control partner.
 Reciprocal social interaction test
 6-7 months
Social approach1
Decreased
Description: Regardless of partner (mutant vs. control), Tshz1 mutant mice exhibited significantly longer latency to enter the partnerâ??s portion of the cage (fold change = 7.57 for control partners; fold change = 3.40 for mutant partners) compared to control mice. However, this latency was reduced by 60.4% when the mutant mouse (subject) was partnered with another mutant rather than a control.
 Reciprocal social interaction test
 6-7 months
Social withdrawal1
Increased
Description: Tshz1 mutant mice paired with other mutants engaged in 3.61-fold more nonsocial behaviors (digging, cage exploration, self-grooming) in a social context, compared to when paired with a control partner. This was also significantly greater than the number of nonsocial behaviors exhibited by control mice when paired with either a control or mutant partner.
 Reciprocal social interaction test
 6-7 months
Aggression1
Decreased
Description: Tshz1 mutant mice displayed significantly fewer aggressive behaviors (biting, chasing) when paired with mutant partner compared to control mice paired with a mutant partner. Control mice exhibited a 3.17-fold increase in aggressive behaviors when paired with mutant mice compared to when paired with a control partner.
 Reciprocal social interaction test
 6-7 months
Depression1
Increased
Description: Tshz1 mutant mice exhibited an 86% increase in the amount of time spent immobile (floating) in the FST compared with control mice.
 Forced swim test
 6-7 months
Anxiety1
Increased
Description: Tshz1 mutant mice exhibited a 31.0% reduction in the time spent in the center of the open field chamber (as opposed to the edges) compared to control mice.
 Open field test
 6-7 months
Exploratory activity1
Decreased
Description: Tshz1 mutant mice exhibited reduced exploratory behavior during the 3 minute habituation period (before stimulus exposure) compared with control mice on day 2. Similar results were seen in a novel environment (day 4), as Tshz1 mutant mice exhibited reduced exploratory behavior during the 3 minute habituation period (before CS exposure).
 Fear conditioning test
 6-11 months
Extinction of fear memory1
Decreased
Description: On day 5, following the initial CS exposure, control mice activity rate was significantly elevated compared with the first CS exposure on day 4. This is indicative of an extinguished fear response. Tshz1 mutant mice, however, moved less than controls in response to the CS and did not exhibit a significantly different response than they did on day 4, suggesting impaired expression of fear extinction.
 Fear conditioning test
 6-11 months
Anxiety1
 No change
 Elevated zero maze test
 6-7 months
Fear response1
 No change
 Fear conditioning test
 6-11 months
Extinction learning1
 No change
 Fear conditioning test
 6-11 months
 Not Reported:

 

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