Two de novo missense variants in the TET2 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.02) (Iossifov et al., 2014; Krumm et al., 2015).
Molecular Function
The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. In addition to its role in DNA demethylation, TET2 isalso involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Variation in DHX genes, including DHX9, has been linked to neurodevelopmental disorders including autism spectrum disorder (ASD). The homozygous knockout model shows no change in viability but exhibits decreased body weight compared to sex-matched wildtypes. The model also shows altered behavioral and neurological function. Male and female model mice show decreased locomotion, with a decrease in distance traveled in the periphery of the open field and a decrease in locomotor speed. Additionally, model male and female mice demonstrate decreased grip strength, increased tremor, and decreased auditory functioning, as measured by the auditory brainstem response test. Furthermore, the model shows altered metabolic function, with possible altered renal function, decreased glucose clearance, and decreased cholesterol levels.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A targeting vector was designed to place an FRT- and loxP-flanked neomycin resistance cassette upstream of exon 3 and a loxP site downstream of exon 3. The construct was electroporated into BAC-BA1(129S/SvEV x C57BL/6)-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. Strong chimeras were identified and crossed to C57BL/6 females to verify germline transmission. The F1 generation was PCR screened and crossed to 129S4/SvJaeSor-Gt(ROSA)26Sortm1(FLP1)Dym/J (JR#003946) to remove the FRT neo cassette.
Allele Type: Conditional knockout
Strain of Origin: (C57BL/6 x 129S/SvEv)F1
Genetic Background: C57BL/6N
ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A transgenic construct containing a human growth hormone polyadenylation signal and a Cre recombinase gene under the control of the promoter and the nervous system-specific enhancer present in the second intron of the rat nestin gene, was injected into B6SJLF2 oocytes. Founder animals were bred to wildtype C57BL/6J mice. The mice were then backcrossed to C57BL/6J for at least six generations. After its arrival at The Jackson Laboratory, it was crossed to C57BL/6J (Stock No. 000664) for another four generations.
Allele Type: Conditional knockout
Strain of Origin: (C57BL/6 x SJL)F2
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
CaMKII-alpha-Cre viruses targeting glutamatergic neurons were bilateraly injected into the LHb of Tet2 loxP/loxP mice at 8 weeks, resulting in Tet2 deficiency in glutamatergic neurons.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source: Jackson Laboratory
Description: Tet2 mutant mice exhibited no change in activity in lateral habenula neurons during the interaction with a stranger mouse compared to an object, while wildtype controls exhibited an increase in activity during the interaction with the stranger mouse compared to the object. Additionally, Tet2 mutant mice exhibited no change in the percentage of ON neurons during social interaction, object sniffing, or self-directed activity, while wildtype mice exhibited a significant increase in the percentage of ON neurons during social interaction compared to the other two behaviors.
Exp Paradigm: lateral habenula neurons
Description: Tet2 male mutant mice exhibited a significant decrease in the time spent exploring a novel mouse (s2) as opposed to a familiar mouse (s1) compared to wildtype controls, suggesting a deficit in social memory.
Exp Paradigm: familiar mouse in chamber 1 (s1), stranger mouse (s2) in chamber 2
Description: Tet2 male mutant mice exhibited a significant decrease in time spent sniffing a stranger mouse (as opposed to an empty cage) compared to wildtype controls, as further exhibited by a significant decrease in social preference index.
Exp Paradigm: stranger mouse (s1) in chamber 1, empty cage (object) in chamber 2
Description: Genes in dynamically hydroxymethylated loci associated with cell leading edge, neuron to neuron synapse, postsynaptic specialization, and glutamatergic and asymmetric synapses were significantly different at the cellular component level.
Exp Paradigm: lateral habenula
Description: Tet2 mutant mice exhibited a significant decrease in Tet2 protein levels in the lateral habenula compared to wildtype controls.
Exp Paradigm: lateral habenula
Description: Tet2 mutant mice exhibited significantly reduced levels of global DNA 5hmC modification in the lateral habenula compared to wildtype controls.
Exp Paradigm: lateral habenula
Description: Tet2 male mutant mice exhibited a significant decrease in time spent sniffing a stranger mouse (as opposed to an empty cage) compared to wildtype controls, as further exhibited by a significant decrease in social preference index.
Exp Paradigm: stranger mouse (s1) in chamber 1, empty cage (object) in chamber 2
Description: Tet2 male mutant mice exhibited a significant decrease in the time spent exploring a novel mouse (s2) as opposed to a familiar mouse (s1) compared to wildtype controls, suggesting a deficit in social memory.
Exp Paradigm: familiar mouse in chamber 1 (s1), stranger mouse (s2) in chamber 2
Description: Tet2 mutant mice exhibited a significant decrease in time spent sniffing a stranger mouse (as opposed to an empty cage) compared to control mice, as further exhibited by a significant decrease in social preference index.
Exp Paradigm: stranger mouse (s1) in chamber 1, empty cage (object) in chamber 2
Description: Tet2 mutant mice displayed 382 differentially expressed genes, including 161 genes that were up-regulated and 221 genes that were down- regulated.
Description: Tet2 mutant mice exhibited significantly reduced levels of global DNA 5hmC modification in the habenula compared to control mice.
Exp Paradigm: habenula
Description: Tet2 mutant mice exhibited a significant reduction in the 5hmC modification of the promoter of the Sh3rf2 gene compared to wildtype control mice.
