A number of de novo variants in the KDM2B gene, including two de novo missense variants, have been identified in ASD probands (Iossifov et al., 2014; Feliciano et al., 2019; Satterstrom et al., 2020). Gao et al., 2022 demonstrated that Kdm2b played a critical role in maintaining neural stem cells (NSCs) in the mouse brain, and that heterozygous adult Kdm2b mutant mice displayed both intellectual disability-like memory deficits and core autistic-like behaviors. van Jaarsveld et al., 2022 described a cohort of 21 individuals with heterozygous and likely pathogenic variants in KDM2B presenting with a neurodevelopmental syndrome characterized by developmental delay and/or intellectual disability, autism, attention deficit disorder/attention deficit hyperactivity disorder, congenital anomalies mainly affecting the heart, eyes, and urogenital system, and subtle facial dysmorphism. Yokotsuka-Ishida et al., 2021 identified a missense variant in the KDM2B gene in a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies, intellectual disability, and schizophrenia. KDM2B has also been proposed to be a contributing gene to phenotypes observed in individuals with 12q24.31 microdeletions (Chouery et al., 2013; Labonne et al., 2016; Krzyzewska et al., 2019).
Molecular Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia
Kdm2b is a transcription factor, and a mutation lacking the CxxC-ZF domain shows embryonic lethality in homozygous form. The heterozygous mutant shows decreased hippocampal size and deficits in hippocampus-dependent tasks, such as novel object recognition and spatial learning. The heterozygous mutant shows upregulation of genes associated with cell cycle arrest and apoptosis. Heterozygote mutants that lack the CxxC-ZF domain have decreased occupancy of the transcription factor on its DNA targets, suggesting that lack of its transcriptional regulatory activity leads to downstream effects on morphology and behavior.
References
Type
Title
Author, Year
Primary
Impaired KDM2B-mediated PRC1 recruitment to chromatin causes defective neural stem cell self-renewal and ASD/ID-like behaviors
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Kdm2b conditional mutant mouse line (MGI:7327329) was generated by inserting two LoxP elements into the exon 13-flanking sites at the Kdm2b gene locus. A Cre recombinase-mediated deletion of exon 13 results in altered splicing of mRNA encoding a mutant KDM2B protein with deletion of amino acids 552-626 encompassing the entire CxxC-ZF domain. The mutant KDM2B protein contains all functional domains except its CxxC-ZF domain and thus lacks its function in recruiting PRC1 to chromatin. The conditional-ready mutant was crossed with a neural progenitor cell-specific Cre (Nestin-Cre) mouse line (MGI:2176173) to generate neural Kdm2b heterozygous conditional mutant mice.
Allele Type: Conditional knockin
Strain of Origin: C57BL/6 x 129; (C57BL/6 x SJL)F2
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Yi Zhang lab; Jackson laboratory
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
The Kdm2b conditional mutant mouse line (MGI:7327329) was generated by inserting two LoxP elements into the exon 13-flanking sites at the Kdm2b gene locus. A Cre recombinase-mediated deletion of exon 13 results in altered splicing of mRNA encoding a mutant KDM2B protein with deletion of amino acids 552-626 encompassing the entire CxxC-ZF domain. The mutant KDM2B protein contains all functional domains except its CxxC-ZF domain and thus lacks its function in recruiting PRC1 to chromatin. The conditional-ready mutant was crossed with a neural progenitor cell-specific Cre (Nestin-Cre) mouse line (MGI:2176173) to generate neural Kdm2b conditional mutant mice. The homozygous conditional mutation results in embryonic lethality.
Allele Type: Conditional knockin
Strain of Origin: C57BL/6 x 129; (C57BL/6 x SJL)F2
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Yi Zhang lab; Jackson laboratory
Description: Kdm2b mutant mice had significantly fewer BrdU-incorporated neural stem cells in the subventricular zone and dentate gyrus of the hippocampus compared with wildtype controls.
Exp Paradigm: BrdU
Description: Kdm2b mutant mice exhibited a decrease in hippocampus size compared to wildtype control mice, with 20% less weight and a significantly reduced hippocampus to whole brain weight ratio.
Description: Kdm2b mutant mice had significantly lower numbers of Sox2-positive neural stem cells in the subventricular zone and dentate gyrus of the hippocampus compared with wildtype controls.
Exp Paradigm: Sox2
Description: Kdm2b mutant mice exhibited a decrease in sociability compared to wildtype controls, as evidenced by no difference in the time spent exploring an object versus a social stimulus. In contrast, wildtype controls exhibited a significant preference for the social stimulus over the object.
Description: Kdm2b mutant mice exhibited a decrease in preference for a socially novel mouse compared to wildtype controls. While wildtype mice spent significantly more time exploring a novel mouse, mutant mice spent similar amounts of time exploring the novel and familiar mouse.
Description: Kdm2b mutant mice exhibited a decrease in the amount of time spent in the platform quadrant compared to wildtype controls during post-training probe tests (p = 0.0098).
Description: Kdm2b mutant mice exhibited a significant delay in spatial learning during the first 5-day acquisition training phase (p = 0.005) of the morris water maze, as evidenced by increased escape latency.
Description: Kdm2b mutant mice exhibited reduced discrimination indexes (t = 2.252, df = 28, p = 0.032) compared to wildtype controls when in the presence of a familiar and novel object, as measured by: (time spent on the novel object - time spent on the familiar object) / total time.
Description: Analysis at the representative Cdkn2a/2b, Bmp7, and Wnt7b gene loci showed that Kdm2b mutant mice exhibited a decrease in KDM2B and RING1B occupancy at the Ink4a-Arf locus.
Description: Kdm2b mutant mouse neural stem cells exhibited highly upregulated levels of Cdkn2a, Cdkn2b,and Cdkn1a, which play a central role in inducing both cell-cycle arrest and p53-mediated apoptosis.
Description: Kdm2b mutant mice were generated by Cre-mediated deletion of exon 13, resulting in altered splicing of the mRNA encoding a mutant KDM2B protein with loss of the CxxC-ZF domain.
Description: Kdm2b mutant mouse neural stem cells had more upregulated (n = 302) than downregulated (n = 191) genes. These upregulated genes are involved in inducing cell apoptosis, repressing cell proliferation, and inducing neural development. The downregulated genes are involved in cell cycle regulation and DNA replication.
Description: Kdm2b mutant mouse neural progenitor cells exhibited a 50% reduction in genome-wide KDM2B occupancy at the 7125 KDM2B-binding sites compared with wildtype controls. Additionally, mutant mouse neural stem cells exhibited a 25% reduction in RING1B occupancy at the promoters of upregulated genes, whereas occupancy at the downregulated gene promoters increased slightly.
Description: Kdm2b homozygous mutant (Kdm2b^2f/2f; Nestin-Cre^+/-) mouse pups were not born in an expected Mendelian ratio, with none produced in the (Kdm2b^2f/2f x Kdm2b^2f/+;Nestin-Cre^+/-) first generation. This suggests the mutation in the developing mouse brain was embryonically lethal.
