Deficiency of <i>CHAMP1</i>, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

Nagai, Masayoshi; Iemura, Kenji; Kikkawa, Takako; Naher, Sharmin; Hagihara, Hideo; Nagata, Koh Ichi; Anzawa, Hayato; Kugisaki, Risa; Wanibuchi, Hideki; Abe, Takaya; Inoue, Kazuaki; Kinoshita, Kengo; Miyakawa, Tsuyoshi; Osumi, Noriko; Tanaka, Kozo

doi:10.1093/braincomms/fcac220

Cited by 5 publications

(4 citation statements)

References 64 publications

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“…In-utero electroporation (IUE) was performed as described previously with slight modification (Nagai et al, 2022). Pregnant WT mice (E14.5) were anesthetized with isoflurane.…”

Section: Methodsmentioning

confidence: 99%

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Naher,

Kikkawa,

Iemura

et al. 2023

Preprint

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Accurate mitotic division of neural stem cell/progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and neurons in the developing cortex. Here, we investigated the pivotal role of Kif23, an N-kinesin motor protein, in embryonic mouse NSPCs. We found that Kif23 is highly expressed in the mitotic NSPCs within the embryonic cortex of both mouse and human. Knockdown (KD) of Kif23 led to precocious neurogenesis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Kif23 KD induced upregulation of the gamma-H2AX-p53-p21 signaling pathway, ultimately culminating in cytokinetic failure. Additionally, Kif23 depletion perturbed the apical surface structure of NSPCs and disrupted the proper localization of apical junctional proteins. Importantly, we demonstrated the successful rescue of Kif23 KD-induced phenotypes by introducing wild-type human KIF23, but not by a variant of KIF23 with a microcephaly-associated mutation. Our findings underscore the critical role of Kif23 in cortical development and provide novel insights into the intricate molecular mechanisms underlying pathogenesis of microcephaly.

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“…In-utero electroporation (IUE) was performed as described previously with slight modification (Nagai et al, 2022). Pregnant WT mice (E14.5) were anesthetized with isoflurane.…”

Section: Methodsmentioning

confidence: 99%

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Naher,

Kikkawa,

Iemura

et al. 2023

Preprint

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“…CVS is also described in 6 of 11 individuals with a pathogenic proteintruncating variant in CHAMP1 (Levy et al, 2022). Knock-out of CHAMP1 in embryonic mouse brain caused downregulation of multiple ion channel genes, including cations (49). POGZ variants cause White-Sutton syndrome, yet another dominant neurodevelopmental disorder with dysmorphic features.…”

Section: Candidate Genes Highly Likely/likely Related To Cvsmentioning

confidence: 99%

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Bar¹,

Ebenau²,

Weiner³

et al. 2023

Front. Neurol.

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ObjectiveTo utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.MethodsA retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. “Qualifying” variants were defined as coding, rare, and conserved. Additionally, “Key Qualifying” variants were Pathogenic/Likely Pathogenic, or “Clinical” based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.ResultsThirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as “Highly likely” (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or “Likely” (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as “Possibly” CVS related.ConclusionAll 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

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“…Disorders associated with CHAMP1 and POGZ mutations also include phenotypes of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), collectively called neurodevelopmental disorders (NDDs) 30,32,33 . Studies using mouse models in which CHAMP1 and POGZ were modified showed that these genes are involved in neuronal development [34][35][36] . Pathogenic variants in CHAMP1 and POGZ are predominantly categorized as heterozygous premature termination codon (PTC) mutations including nonsense and frameshift mutations, resulting in the production of truncated proteins lacking the C-terminal region [25][26][27][28][29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

CHAMP1 premature termination codon mutations found in individuals with intellectual disability cause a homologous recombination defect through haploinsufficiency

Yoshizaki,

Ouchi,

Kurniawan

et al. 2024

Preprint

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CHAMP1 (chromosome alignment-maintaining phosphoprotein 1) plays a role in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). The CHAMP1 gene is one of the genes mutated in individuals with intellectual disability. The majority of the mutations are premature termination codon (PTC) mutations, while missense mutations have also been reported. How these mutations affect the functions of CHAMP1 has not been clarified yet. Here we investigated the effects of the CHAMP1 mutations on HR. In B lymphocytes and fibroblasts derived from individuals with CHAMP1 PTC mutations, truncated CHAMP1 proteins of the expected sizes were detected. When DSBs were induced in fibroblasts with PTC mutations, a defect in HR was detected. U2OS cells expressing the CHAMP1 mutants did not show an HR defect in the presence of endogenous wild-type (WT) CHAMP1, whereas they were unable to restore HR activity when WT CHAMP1 was depleted, suggesting that the PTC mutations are loss-of-function mutations. On the other hand, the CHAMP1 mutants with missense mutations restored HR activity when WT CHAMP1 was depleted. In DLD-1 cells, heterozygous depletion of CHAMP1 resulted in an HR defect, indicating haploinsufficiency. These results suggest that CHAMP1 PTC mutations cause an HR defect through a haploinsufficient mechanism, while CHAMP1 missense mutations do not affect the HR function of CHAMP1.

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Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

Cited by 5 publications

References 64 publications

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Kinesin family member Kif23 regulates cytokinetic division and maintains neural stem/progenitor cell pool in the developing neocortex

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

CHAMP1 premature termination codon mutations found in individuals with intellectual disability cause a homologous recombination defect through haploinsufficiency

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