1p21.3 microdeletions affecting MIR137 have been identified in individuals with ASD (Carter et al., 2011), intellectual disability (Willemsen et al., 2011), and syndromic obesity (D'Angelo et al., 2015; Tucci et al., 2016). MIR137 resides within a locus on chromosome 1p21.3 that was found to be highly associated with schizophrenia in meta-analyses combining multiple genome-wide association studies (Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium 2011; Cross-Disorder Group of the Psychiatric Genomics Consortium 2013; Ripke et al., 2013; Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014). A rare functional enhancer variant approximately 3.6 kb upstream of MIR137 (1:g.98515539A>T) was found to be associated with schizophrenia and bipolar disorder (Duan et al., 2014). Partial loss of Mir137 in heterozygous conditional-knockout mice was found to result in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior; treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorated these deficits (Cheng et al., 2018).
Molecular Function
microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder.
Mice with homozygous germline KO of miR-137 or neural selective CKO show postnatal lethality with decrease in body and brain size, while heterozygotes show deficits in synaptic plasticity and learning, repetitive behavior, impaired social interaction, and elevated PDE10a. Treatment with Pde10a or KD of Pde10a rescues deficits in mir137 HT mice.
References
Type
Title
Author, Year
Primary
Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mir137 gene was disrupted via homologous recombination in ES cells, where two loxP sites were inserted -2kb unstream and -0.6kb downstream of the Mir137 gene. Conditional ready mice were crossed with Zp3-Cre mic to delete Mir137 in the germline.
Allele Type: Knockout
Strain of Origin: Not reported
Genetic Background: 129S6/SvEvTac
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mir137 gene was disrupted via homologous recombination in ES cells, where two loxP sites were inserted -2kb unstream and -0.6kb downstream of the Mir137 gene. Conditional ready mice were crossed with Zp3-Cre mic to delete Mir137 in the germline.
Allele Type: Knockout
Strain of Origin: Not reported
Genetic Background: 129S6/SvEvTac
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of the microRNA Mir137 gene using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Not reported
Genetic Background: 129S6/SvEvTac
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of the microRNA Mir137 gene using Nestin-Cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Not reported
Genetic Background: 129S6/SvEvTac
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Mutants show increase in psd95 and synaptophysin immunofluorescence intensity compared with controls in the hippocampus ca1, indicating synaptic overgrowth.
Exp Paradigm: NA
Description: Mutants show differentially expressed genes compared with controls. upregulated proteins were involved in dna replication, nervous system development, and chromatin remodeling. downregulated proteins were involved in peptidase activity regulation, acute-phase response, and regulation of neurotransmitter secretion. gria3, gabrb1 and psd-95 core complex genes are downregulated in mutant brains. fam3c, pde10a, epha7, foxp1, shroom2, are upregulated.
Exp Paradigm: NA
Description: Mutants show increase in psd95 and synaptophysin immunofluorescence intensity compared with controls in the hippocampus ca1, indicating synaptic overgrowth.
Exp Paradigm: NA
Description: Mutants show no change in time spent with a familiar social stimulus over a non-familiar social stimulus compared with controls.
Exp Paradigm: NA
Description: Mutants show increase in spine density in the hippocampus ca1 region compared with controls, indicating a deficiency in pruning.
Exp Paradigm: NA
Description: Mutants show significant reduction in ppf at the 50ms interval compared with controls but not at 20, 100, 200 or 400ms intervals.
Exp Paradigm: NA
Description: Mutants show decrease in e/i ratio compared with controls.
Exp Paradigm: Epscs and ipscs were pharmacologically isolated by using inhibitors specific to glutamate or gaba receptors. e/i ratios by sequentially recording evoked synaptic responses, first in the absence of any inhibitors to obtain total synaptic currents (that is, epsc + ipsc), second in the presence of nbqx or apv to obtain ipsc, and finally in the presence of nbqx, apv, or picrotoxin to verify the ipsc component.
Description: Mutants show no change in time spent with a familiar social stimulus over a non-familiar social stimulus compared with controls.
Exp Paradigm: NA
