Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia

Yokotsuka-Ishida, Saeko; Nakamura, Masayuki; Tomiyasu, Yoko; Nagai, Mio; Kato, Yuko; Tomiyasu, Akiyuki; Umehara, Hiromi; Hayashi, Takuo; Sasaki, Natsuki; Ueno, Shu‐ichi; Sano, Akira

doi:10.1038/s10038-020-00889-4

Cited by 8 publications

(6 citation statements)

References 38 publications

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“…Previously, a role for USP7 in endosomal protein recycling via stabilization of MAGEL2-TRIM27 was proposed to contribute to Hao-Fountain syndrome ( 7 ). We note, however, that USP7 is a predominantly nuclear protein and mutations in several of its nuclear targets, including, e.g., BCOR, RING1A, KDM2B, and ERCC6, have been implicated in a variety of neurodevelopmental syndromes ( 26 , 54 – 57 ). Last, USP7 regulates the expression of developmental genes, such as AUTS2 , that play important roles in neurodevelopment and autism spectrum disorders ( 26 , 47 ).…”

Section: Discussionmentioning

confidence: 84%

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

et al. 2022

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Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.

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Section: Discussionmentioning

confidence: 84%

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

et al. 2022

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“…Variants in individuals/families 24, 25, 29, 30, and 34 were identified as described before. 19 , 20 , 22 , 24 The variant in individual 4.3 was identified through targeted Sanger sequencing. All other variants were detected through clinical and/or research-based exome sequencing.…”

Section: Methodsmentioning

confidence: 99%

“… 19 – 21 In addition, 2 sporadic patients and 1 family with heterozygous KDM2B missense variants have been described. 22 – 24 A monogenic KDM2B -related human disorder has however not been delineated, and the significance of the reported variants remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

Jaarsveld

Reilly

Cornips

et al. 2023

Genetics in Medicine

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“…The long isoform of KDM2B – KDM2BLF – contains a Jmjc demethylation domain which removes the di-methylated lysine 36 of histone H3 (H3K36me2) to regulate pluripotency and early embryogenesis(Huo et al, 2022). Mutations of human KDM2B gene are associated with neurodevelopment defects including intellectual disability (ID), speech delay and behavioral abnormalities(Labonne et al, 2016; van Jaarsveld et al, 2022; Yokotsuka-Ishida et al, 2021). A recent study indicated that heterozygosity of Kdm2b in mice impaired neural stem cell self-renewal and leads to ASD/ID-like behaviors(Y.…”

Section: Introductionmentioning

confidence: 99%

KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors

Zhang

Zhao

Shen

et al. 2023

Preprint

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The hippocampus plays major roles in learning and memory. Similar to other parts of the brain, the development of hippocampus requires precise coordination of patterning, cell proliferation, differentiation, and migration, with both cell-intrinsic and extrinsic mechanisms involved. Here we genetically removed the chromatin-association capability of KDM2B - a key component of the variant Polycomb repressive complex 1 (PRC1) - in the progenitors of developing dorsal telencephalon (Kdm2bΔCxxC) to surprisingly discover that the size of Kdm2bΔCxxC hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2bΔCxxC mice displayed prominent defects in spatial memory, motor learning and fear conditioning. The differentiation trajectory of the developing Kdm2bΔCxxC hippocampus was greatly delayed, with a significant amount of TBR2-expressing intermediate progenitors stuck along the migratory/differentiation path. Transcriptome and chromatin immunoprecipitation studies of neonatal hippocampi and their progenitors indicated that genes implicated in stemness maintenance, especially components of canonical Wnt signaling, could not be properly silenced by PRC1 and PRC2. Activating the Wnt signaling disturbed hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveiled a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of hippocampus during development.

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Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia

Cited by 8 publications

References 38 publications

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature

KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors

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