Screening of 9q33.1 copy number variants disrupting ASTN2 or both ASTN2 and TRIM32 in clinical microarray data from 89,986 individuals across 10 sites, including 64,114 subjects with neurodevelopmental disorders (NDD), in Lionel et al., 2014 found that deletions affecting both ASTN2 and TRIM32 were statistically enriched in NDD cases compared to controls (23 deletions in 64,114 cases vs. 6 in 44,085 controls; P-value 0.019); this enrichment was subsequently determined to be male-specific [22 deletions in 40,438 NDD males vs. 2 deletions in 14,953 male controls (P-value 0.024) compared to 1 deletion in 23.676 NDD females vs. 3 deletions in 18.218 female controls (P-value 0.964)]. Zhu et al., 2019 found that absence of TRIM32 resulted in impaired generation of GABAergic interneurons and autism-like behaviors in mice via suppressed mTOR signaling.
Molecular Function
The protein encoded by this gene is a member of the tripartite motif (TRIM) family and has an E3 ubiquitin ligase activity. The protein localizes to cytoplasmic bodies and has also been localized to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.
In mice, deficiency of TRIM32 results in decreased proliferation of GABAergic interneurons, increased autophagy, and autism-like behaviors in mice including decreased social interaction, increased repetitive behaviors, and hyperactivity. Increased autophagy in TRIM32 KO mice can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32 KO mice.
References
Type
Title
Author, Year
Primary
Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The 5 kb genomic fragment containing exon 2 of TRIM32 was replaced with an SA-IRES-beta-geopA expression cassette.
Allele Type: Knockout
Strain of Origin: 129S1
Genetic Background: 129S1
ES Cell Line: Not specified
Mutant ES Cell Line: R1 ES cells
Model Source: Nicklas et al, 2012 (PMID 22299041)
Model Type:
RESCUE-Transplantation
Model Genotype:
Homozygous
Mutation:
M/LGE progenitors were transplated into Trim32 deficient mice. 10^4 cultured L/MGE progenitors derived from E13.5 EGFP transgenic mouse (Jax lab 003291) were injected bilaterally into two sites of the hippocampus of 3-week-old mice, which could differentiate into GABAergic interneurons after transplantation. Sandimmun (cyclosporin) was intraperitoneally injected twice per day before and after transplantation, then once per day during the first 15 days after transplantation, and every two days then after at 5 microg/g.
Allele Type: Knockout
Strain of Origin: 129S1
Genetic Background: 129S1
ES Cell Line: Not specified
Mutant ES Cell Line: R1 ES cells
Model Source: Nicklas et al, 2012 (PMID 22299041)
Description: Quantification of cerebellar outline area showed that the cerebellar area of trim32â??/â?? mice was significantly smaller than area of wt mice
Exp Paradigm: HandE staining sagittal sections
Description: Distal dendritic arborization of pcs was obviously decreased in trim32â??/â?? mice, as compared with wt mice although there was a slight increase in proximal dendritic arborization
Exp Paradigm: Golgi-Cox staining
Description: Mild decrease in size of cerebella; no overt gross morphological alternations between mid-aged trim32â??/â?? and wt littermate cerebella
Exp Paradigm: Macroscopic images
Description: Mutants show decrease in proliferation of neural precursor cells in the lge and mge. mutants show decrease in phosphohistone h3 positive cells in the mge at e13.5. mutants show decrease in nkx2.1 positive interneuron progenitors in the mge.
Exp Paradigm: H3, nkx2.1
Description: Mutants show decreased numbers of brdu+gaba+ cells born at e13.5 in the hippocampus and the cortex at p18, and decreased numbers of gaba+ and glutamate decarboxylase 67 positive cells in the dentate gyrus at 3 weeks and 4 months. mutants show decrease in the numbers of interneuron subtypes including parvalbumin, calretinin, neuropeptide y, and somatostatin interneuron subtypes in the hippocampus at 3 weeks and 4 months.
Exp Paradigm: Gaba, gad67, pv, clr, npy, sst
Description: Quantified the thickness of the cerebellar ml and found it was thinner in trim32â??/â?? cerebella compared with the cerebella in wt littermates
Exp Paradigm: HandE staining sagittal sections
Description: Mean fluorescence intensity of vglut1-positive parallel fiber-purkinje cell connections and the number of vglut2-positive climbing fiber-purkinje cell connections were reduced in trim32â??/â?? mice
Description: Mutants show increased frequency of epileptic spikes in the hippocampus and cortex, indicating hyperexcitability and e/i imbalance.
Exp Paradigm: NA
Description: Mutants show increase in the levels of microtubule-associated protein 1 light chain 3 (lc3)-ii, an indicator for formation of autophagosomes, in the embryonic mge. this increase of lc-ii is not blocked by chloroquine indicating the increase in lc-ii is not due to impaired autophagic influx.
Exp Paradigm: NA
