Multiple de novo variants in the ZBTB18 gene, including two de novo loss-of-function (LoF) variants, have been reported in ASD probands (De Rubeis et al., 2014; Feliciano et al., 2019; Wang et al., 2020; Zhou et al., 2022; Trost et al., 2022; More et al., 2023). A case-control mutation burden analysis of 16,000 cases with neurodevelopmental disorders and nonpsychiatric controls from ExAC in Wang et al., 2020 identified ZBTB18 as a gene showing a significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%). Heterozygous mutations in the ZBTB18 gene are responsible for autosomal dominant intellectual developmental disorder-22 (MRD22; OMIM 612337), a disorder characterized by impaired intellectual development with frequent cooccurrence of corpus callosum anomalies, hypotonia, microcephaly, growth problems, and variable facial dysmorphism; stereotypies have been reported in a subset of affected individuals (Lopes et al., 2016; Cohen et al., 2017; Depienne et al., 2017; Trinh et al., 2019).
Molecular Function
This gene encodes a C2H2-type zinc finger protein which acts a transcriptional repressor of genes involved in neuronal development. The encoded protein recognizes a specific sequence motif and recruits components of chromatin to target genes.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
The transcriptional repressor Zbtb18 is crucial for cell-division patterning and neuronal survival in the developing cortex. Haploinsufficient mutation results in agenesis of the corpus callosum. Behaviorally, the mutants show deficits in the rotarod test, in spontaneous alternation, and in the reversal task in the Morris water maze. Although the mutants show normal high-frequency stimulation (HFS)-induced long term potentiation, they exhibit an earlier saturation after multiple trains of HFS, meaning that the potentiation reaches a lower ceiling than in the mutant in this paradigm.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Exon 1 was replaced with a neo cassette. The absence of protein expression was confirmed by western blot analysis on embryonic brain extracts (MGI:3851929).
Allele Type: Knockout
Strain of Origin: 129/Sv
Genetic Background: C57BL/6J
ES Cell Line: GS1
Mutant ES Cell Line: Model Source: Haruo Okado lab (PMID 19409883)
Description: Zbtb18 mutant mice displayed decreased latency to fall in trials 4 and 5 (with no change in trials 1-3) compared to wildtype control mice.
Description: Zbtb18 mutant mice exhibited decreased expression of GluA1, and no change in expression of GluA2, GluA3, or GluA4 subunits compared to wildtype control mice.
Description: Zbtb18 mutant mice exhibited no differences in distribution of spine length and spine width (long thick, short thick, long thin, short thin as a percentage of total spines) of CA1 pyramidal neurons compared to wildtype control mice. However, mutant mice exhibited thinner spine head and shorter spine length in the category of the thick spine (which is defined by spine width as more than 0.6 μm), compared with wildtype controls. In the category of the thin spine (defined by spine width less than 0.6 μm), there were no differences in spine head width and spine length.These results suggest that the characteristics of the matured spines in mutant mice are different from those of wildtype control mice.
Exp Paradigm: Zbtb18 mutant mice crossed with Thy1-GFP transgenic mice
Description: Zbtb18 mutant mice exhibited agenesis (developmental failure) of the corpus callosum compared to wildtype control mice.
Exp Paradigm: Kluver-Barrera histochemistry
Description: Zbtb18 mutant mice exhibited decreased expression of GluN1 and GluN2A subunits, and no change in GluN2B subunits, compared to wildtype control mice.
Description: Zbtb18 mutant mice exhibited a decrease in the current-voltage (I-V) curve of NMDAR-excitatory postsynaptic currents compared to wildtype controls.
Description: Zbtb18 mutant mice exhibited early saturation of long-term potentiation compared to wildtype control mice. LTP was saturated via repeated application of tetanic stimulation (100 Hz, 1 s) until no more potentiation was observed.
Description: Zbtb18 mutant mice exhibited a significant decrease in the amount of time spent in the light compartment compared to wildtype control mice.
Description: Zbtb18 mutant mice exhibited longer escape latency than compared to wildtype control mice during the reversal test, indicating that mutant mice exhibit an impairment in cognitive memory flexibility.
Description: Zbtb18 mutant mice exhibited a decrease in mRNA expression in the cerebral cortex and hippocampus by approximately 40% compared to wildtype controls.
