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
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.
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)
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)
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)
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
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
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
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
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
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
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
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
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
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.
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.
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.
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.
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.
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.
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).
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.
