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Relevance to Autism

Caubit et al., 2016 evaluated 7 new patients and 15 previously reported cases with 19q12-q13.11 deletions and determined that TSHZ3 lies within the minimal region of overlap for 19q12-q13.11 deletions found in patients with neurodevelopmental disorders, including ASD. Tshz3 +/- mice display altered corticostriatal synaptic transmission and plasticity and autism-like behavioral defects (Caubit et al., 2016).

Molecular Function

This gene encodes a zinc-finger transcription factor involved in developmental processes.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.
ASD, ID
Support
Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors
ASD
Support
Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior.
Support
Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.
ASD
Support
Integrating de novo and inherited variants in 42
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN850R001 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN850R002 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN850R003 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN850R004 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN850R005 
 copy_number_loss 
  
  
 Familial 
 Paternal 
  
 GEN850R006 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN850R007 
 intergenic_variant 
 C>T 
  
  
  
 Unknown 
 GEN850R008 
 synonymous_variant 
 c.2661C>T 
 p.Pro887%3D 
 De novo 
  
 Simplex 
 GEN850R009 
 missense_variant 
 c.1288G>A 
 p.Val430Ile 
 De novo 
  
 Simplex 
 GEN850R010 
 stop_gained 
 c.250C>T 
 p.Arg84Ter 
 De novo 
  
 Multiplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Duplication
 1
 
19
Duplication
 1
 
19
Deletion-Duplication
 11
 
19
Duplication
 3
 

Model Summary

Tshz3 null mice die at birth due to respiratory failure. Tshz3 heterozygous mice also display increased perinatal lethality, the ones that survive display increased repetitive behavior (digging and nose poking) and anxiety and impaired social approach and memory.

References

Type
Title
Author, Year
Primary
TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.
Additional
Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

M_TSHZ3_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Exon 2 of Tshz3 gene is replaced with a lacZ and neo cassette leading to a loss of TSHZ3 protein expression, after germline transmission the mice were bred to homozygosity.
Allele Type: Targeted (knockout, marker)
Strain of Origin:
Genetic Background: CD1
ES Cell Line:
Mutant ES Cell Line:
Model Source: PMID: 20631175

M_TSHZ3_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Exon 2 of Tshz3 gene is replaced with a lacZ and neo cassette leading to a loss of TSHZ3 protein expression, after germline transmission the heterozygous mice were maintained in a CD1 * CBA/H GNC background.
Allele Type: Targeted (knockout, marker)
Strain of Origin:
Genetic Background: CD1*CBA/H GNC
ES Cell Line:
Mutant ES Cell Line:
Model Source: PMID: 20631175

M_TSHZ3_3_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Floxed exon 2 of Tshz3 was deleted via conditional knockout with Emx1-Cre driver to target cortical projection neurons and glial cells.
Allele Type: conditional knockout
Strain of Origin: 129/SvEvTac
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source: Tshz3 flox from Laurent Fasano Lab (PMID 31060802); Emx1-Cre Kevin R. Jones Lab (PMID 12151506)

M_TSHZ3_4_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Floxed exon 2 of Tshz3 was deleted via conditional knockout with Chat-Cre driver to target striatal cholinergic interneurons.
Allele Type: conditional knockout
Strain of Origin: 129/SvEvTac
Genetic Background:
ES Cell Line:
Mutant ES Cell Line:
Model Source: Tshz3 flox from Laurent Fasano Lab (PMID 31060802); ChAT-Cre from Bradford B. Lowell Lab (PMID 21284986)

M_TSHZ3_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality: neonatal1
Increased
Description: Tshz3 null embryos are unable to breathe at p0 and die with 100% penetrance
Exp Paradigm: NA
 Survival analysis
 P0
Gene expression1
Abnormal
Description: Tshz3 null embryos have several genes upregulated or downregulated in pathways involved in neuronal differentiation and axogenesis and show a diverse expression pattern as markers of different layers of cortical neurons
Exp Paradigm: NA
 Rna sequencing
 E18.5
Anatomical projections and connectivity1
 No change
 Immunostaining
 E18.5
Cortical lamination1
 No change
 Immunostaining
 E18.5
Neuronal number1
 No change
 Immunostaining
 E18.5
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_TSHZ3_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Presynaptic function: paired-pulse facilitation1
Decreased
Description: Paired pulse ration of ampa receptor mediated excitatory postsynaptic currents is lower in msns from tshz3 hets compared to littermate controls
Exp Paradigm: NA
 Whole-cell patch clamp
 P21-28
Synaptic plasticity: striatal ltp1
Increased
Description: Striatal ltp is enhanced in slices from tshz3 hets compared to slices from controls
Exp Paradigm: NA
 Whole-cell patch clamp
 P21-28
Repetitive nose pokes1
Increased
Description: Tshz3 hets performed a higher number of stereotyped dips even when the total number of nose dips was similar to controls
Exp Paradigm: NA
 Hole-board test
 2.5-3 months
Repetitive digging1
Increased
Description: Tshz3 hets have display increased digging in the marble-burying test
Exp Paradigm: NA
 Marble-burying test
 2.5-3 months
Social approach1
Decreased
Description: Tshz3 hets show no preference for stimulus mouse over object in the modified three chamber test for social approach
Exp Paradigm: NA
 Three-chamber social approach test
 2.5-3 months
Social memory1
Decreased
Description: Tshz3 hets show no preference for novel stimulus mouse over familiar mouse
Exp Paradigm: NA
 Three-chamber social approach test
 2.5-3 months
Urinary system development1
Decreased
Description: Tshz3 hets have increased presentation of unilateral hydroureter (about one fourth of embryos starting at e16.5)
Exp Paradigm: NA
 Histology
 >e16.5
Mortality/lethality: neonatal1
Increased
Description: Tshz3 hets show increased neonatal lethality which is reported to be 100% in c57bl/6 background and around 50% in cd1/cba/h gnc background
Exp Paradigm: NA
 Survival analysis
 P0-p10
Anxiety1
Increased
Description: Tshz3 hets display increased anxiety in parameters measured in two tests, including reduced time spent in the central zone of the open field and in the open arms of the elevated plus maze
Exp Paradigm: Elevated plus maze test
 Elevated plus maze test
 2.5-3 months
Exploratory activity1
Decreased
Description: Tshz3 hets display reduced exploratory activity in the open field test assessed by number of zone crossings
Exp Paradigm: NA
 Open field test
 2.5-3 months
Anxiety1
Increased
Description: Tshz3 hets display increased anxiety in parameters measured in two tests, including reduced time spent in the central zone of the open field and in the open arms of the elevated plus maze
Exp Paradigm: Open field test
 Open field test
 2.5-3 months
Exploratory activity: habituation1
 No change
 Three-chamber social approach test
 2.5-3 months
Olfactory learning and memory1
 No change
 Olfactory habituation-dishabituation test
 2.5-3 months
General locomotor activity: ambulatory activity1
 No change
 Open field test
 2.5-3 months
Anatomical projections and connectivity1
 No change
 Neuronal tracing
 1.6 months
Action potential property: firing rate1
 No change
 Whole-cell patch clamp
 P21-28
Intrinsic membrane properties1
 No change
 Whole-cell patch clamp
 P21-28
Spontaneous post synaptic event amplitude: excitatory currents1
 No change
 Whole-cell patch clamp
 P21-28
Spontaneous post synaptic event frequency: excitatory currents1
 No change
 Whole-cell patch clamp
 P21-28
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
 No change
 Whole-cell patch clamp
 P21-28
Ear twitch reflex or preyer's reflex1
 No change
 Preyer's reflex test
 2.5-3 months
Visual placing reflex1
 No change
 Visual placing test
 2.5-3 months
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Maternal behavior, Molecular profile, Physiological parameters, Seizure

M_TSHZ3_3_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: spine density1
Decreased
Description: Spine density of L5 cortical projection neurons from Emx1-driven Tshz3 cKO mice is significantly reduced compared to control mice.
Exp Paradigm: Thy1-GFP-M
 Immunohistochemistry
 P28
Synaptic plasticity: striatal ltd1
Decreased
Description: Long-term depression at corticostriatal synapses is abolished in Emx1-driven Tshz3 cKO mice.
 Whole-cell patch clamp
 P21-28
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
Decreased
Description: Emx1-driven Tshz3 cKO mice show a decreased NMDA/AMPA ratio in cortical projection neurons but unchanged in striatal spiny projection neurons.
 Whole-cell patch clamp
 P21-28
Voltage sensitivity of n-methyl d-aspartate (nmda) receptors1
Decreased
Description: Emx1-driven Tshz3 cKO mice show significantly reduced NMDA-induced currents in cortical projection neurons but unchanged in striatal spiny projection neurons.
 Whole-cell patch clamp
 P21-28
Miniature post synaptic current frequency: excitatory1
Decreased
Description: In Emx1-driven Tshz3 cKO mice, mEPSC frequency is reduced in cortical projection neurons, suggesting decreased action potential-independent glutamate release or reduced number of active excitatory synapses, but no significant change in mEPSC frequency is seen in striatal spiny projection neurons.
 Whole-cell patch clamp
 P21-28
Synaptic plasticity: striatal ltp1
Decreased
Description: Long-term potentiation at corticostriatal synapses is abolished in Emx1-driven Tshz3 cKO mice.
 Whole-cell patch clamp
 P21-28
Social memory1
Decreased
Description: Emx1-driven Tshz3 cKO mice show decreased preference for novel social stimulus conspecific.
Exp Paradigm: Modified without central chamber as a two-chamber test
 Three-chamber social approach test
 P71-87
Social approach1
Decreased
Description: Emx1-driven Tshz3 cKO mice show decreased preference for social stimulus conspecific.
Exp Paradigm: Modified without central chamber as a two-chamber test
 Three-chamber social approach test
 P71-87
Targeted expression1
Decreased
Description: Emx1-driven Tshz3 cKO mice show a drastic reduction of Tshz3 mRNA levels in the cerebral cortex
 Semi-quantitative PCR (qRT-PCR)
 P28
Targeted expression1
Decreased
Description: Emx1-driven Tshz3 cKO mice show a drastic reduction of the density of TSHZ3-positive cells among glutamatergic cortical projection neurons (CPNs) and glial cells while TSHZ3-positive neuron density is unchanged among GABAergic neurons
Exp Paradigm: GAD67-GFP
 Immunohistochemistry
 P28-34
Exploratory activity: habituation1
 No change
 Three-chamber social approach test
 P71-87
Spatial learning1
 No change
 Morris water maze test
 P71-87
Spatial reference memory1
 No change
 Morris water maze test
 P71-87
General locomotor activity: ambulatory activity1
 No change
 Open field test
 P71-87
Motor coordination and balance1
 No change
 Horizontal ladder test
 P71-87
Rearing behavior1
 No change
 Open field test
 P71-87
Cortical lamination1
 No change
 Immunohistochemistry
 P28-34
Neuronal number1
 No change
 Immunohistochemistry
 P28-34
Neuronal number: interneurons1
 No change
 Immunohistochemistry
 P28-34
Intrinsic membrane properties1
 No change
 Whole-cell patch clamp
 P21-28
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 P21-28
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 P21-28
Head bobbing1
 No change
 Hole-board test
 P71-87
Repetitive digging1
 No change
 Burrowing test
 P71-87
Repetitive digging1
 No change
 Marble-burying test
 P71-87
Hearing1
 No change
 Preyer's Reflex test
 P71-87
Olfaction1
 No change
 Olfactory habituation-dishabituation test
 P71-87
Vision1
 No change
 Forepaw reaching test
 P71-87
 Not Reported:

M_TSHZ3_4_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Rearing behavior1
Increased
Description: ChAT-driven Tshz3 cKO mice show increased leaning behavior (rearing) in an open field.
 Open field test
 P71-87
Motor coordination and balance1
Decreased
Description: ChAT-driven Tshz3 cKO mice show impaired hind paw coordination.
 Horizontal ladder test
 P71-87
Spontaneous post synaptic event frequency: inhibitory currents1
Decreased
Description: ChAT-driven Tshz3 cKO mice show decreased mean frequency of spontaneous action potential discharge, and increased irregularity or coefficient of variation of the inter-action potential interval.
 Whole-cell patch clamp
 P21-28
Spontaneous post synaptic event amplitude: inhibitory currents1
Increased
Description: ChAT-driven Tshz3 cKO mice show increased voltage sag amplitude.
 Whole-cell patch clamp
 P21-28
Epsp-spike relationship1
Abnormal
Description: ChAT-driven Tshz3 cKO mice show slight but significant increase in input resistance.
 Whole-cell patch clamp
 P21-28
Repetitive digging1
Increased
Description: ChAT-driven Tshz3 cKO mice show increased marble burying behavior.
 Marble-burying test
 P71-87
Repetitive digging1
Increased
Description: ChAT-driven Tshz3 cKO mice show increased burrowing behavior in a novel cage.
 Burrowing test
 P71-87
Head bobbing1
Increased
Description: ChAT-driven Tshz3 cKO mice show increased stereotyped dips on a hole board.
 Hole-board test
 P71-87
Targeted expression1
Decreased
Description: ChAT-driven Tshz3 cKO mice show decreased density of TSHZ3-positive cells among striatal cholinergic interneurons.
Exp Paradigm: Rosa26-STOP-Tomato
 Immunohistochemistry
 P28-34
Exploratory activity: habituation1
 No change
 Three-chamber social approach test
 P71-87
Spatial learning1
 No change
 Morris water maze test
 P71-87
Spatial reference memory1
 No change
 Morris water maze test
 P71-87
General locomotor activity: ambulatory activity1
 No change
 Open field test
 P71-87
Neuronal number1
 No change
 Immunohistochemistry
 P28-34
Hearing1
 No change
 Preyer's Reflex test
 P71-87
Olfaction1
 No change
 Olfactory habituation-dishabituation test
 P71-87
Vision1
 No change
 Forepaw reaching test
 P71-87
Social approach1
 No change
 Three-chamber social approach test
 P71-87
Social memory1
 No change
 Three-chamber social approach test
 P71-87
 Not Reported:

 

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