CHAMP1 disorder is associated with a complex neurobehavioral phenotype including autism, ADHD, repetitive behaviors and sensory symptoms

Levy, Tess; Lerman, Bonnie; Halpern, Danielle; Frank, Yitzchak; Layton, Christina; Zweifach, Jessica; Siper, Paige M.; Buxbaum, Joseph D.; Kolevzon, Alexander

doi:10.1093/hmg/ddac018

Cited by 11 publications

(22 citation statements)

References 45 publications

(29 reference statements)

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“…Recently, a comprehensive evaluation of the neurobehavioural phenotype of individuals with CHAMP1 mutations was reported. 10 In our behavioural test battery, CHAMP1 +/− mice showed a relatively mild phenotype in a subset of tests. However, a slightly cued memory impairment in the cued and contextual fear conditioning test, as well as a slight working memory impairment in the T -maze test are consistent with ID, as memory deficits are commonly seen in mouse models of ID and ASD genes, such as Fmr1 , Shank and Mecp2 .…”

Section: Discussionmentioning

confidence: 83%

“…Abnormal findings in a rotarod test may also be related to depression-like behaviour. Interestingly, anxiety and depression were frequently manifested in individuals with CHAMP1 mutations, 10 suggesting that depression-like behaviour is a characteristic phenotype of CHAMP1 deficiency. Pathophysiological significance of increased PPI in CHAMP1 +/− mice is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“… 7–9 A recent report showed that disorders associated with CHAMP1 mutations also include ASD and ADHD phenotypes. 10 We originally reported that this gene product is involved in the maintenance of kinetochore–microtubule attachment on the spindle during mitosis and designated the molecule as CAMP ( c hromosome a lignment- m aintaining p hosphoprotein), 11 registered as CHAMP1 in Human Gene Nomenclature Database. CHAMP1 (CAMP) is conserved in vertebrates, and human CHAMP1 is an 812 aa protein composed of a large intrinsically disordered region with zinc-finger domains at each end ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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

Nagai

Iemura

Kikkawa

et al. 2022

Brain Communications

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CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore–microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioral test battery, adult CHAMP1 heterozygous-knockout mice showed mild memory defects, altered social interaction, and depression-like behaviors. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Nagai

Iemura

Kikkawa

et al. 2022

Brain Communications

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“…CHAMP1, or chromosome alignment maintaining phosphoprotein 1, is a gene located on the long arm of chromosome 13 and mutations in the gene are associated with CHAMP1-related neurodevelopmental disorder, or CHAMP1 disorder (Garrity 2021;Hempel 2015;Isidor 2016;Itoh 2011;Levy 2022b;Tanaka 2016). There are only a modest number of published reports on CHAMP1 disorder, but analysis of over 1000 individuals serially ascertained for intellectual or developmental delay (IDD) indicate that as many as 1 in 500 individuals with IDD may carry mutations in this gene (Disorders.…”

Section: Introductionmentioning

confidence: 99%

“…For example, both PTCs in SHANK3 and deletions encompassing SHANK3 produce overlapping phenotypes, consistent with a LoF mechanism (De Rubeis 2018;Fu 2022;Levy 2022a). In the current report, we carried out targeted phenotyping of individuals with 13q3 deletions that included CHAMP1 or with CHAMP1 mutations, using methods that we have reported for individuals with CHAMP1 mutations (Levy 2022b). This allowed us to directly compare phenotypes in individuals with 13q3 deletions with those with CHAMP1 mutations to determine whether the results are consistent with CHAMP1 PTC mutations operating through a LoF mechanism.…”

Section: Introductionmentioning

confidence: 99%

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations do not act through haploinsufficiency

Levy

Pichardo

Silver

et al. 2023

Preprint

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CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q3 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

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Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency

et al. 2023

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CHAMP1 disorder is a genetic neurodevelopmental condition caused by mutations in the CHAMP1 gene that result in premature termination codons. The disorder is associated with intellectual disability, medical comorbidities, and dysmorphic features. Deletions of the CHAMP1 gene, as part of 13q34 deletion syndrome, have been briefly described with the suggestion of a milder clinical phenotype. To date, no studies have directly assessed differences between individuals with mutations in CHAMP1 to those with deletions of the gene. We completed prospective clinical evaluations of 16 individuals with mutations and eight with deletions in CHAMP1. Analyses revealed significantly lower adaptive functioning across all domains assessed (i.e., communication, daily living skills, socialization, and motor skills) in the mutation group. Developmental milestones and medical features further showed difference between groups. The phenotypes associated with mutations, as compared to deletions, indicate likely difference in pathogenesis between groups, where deletions are acting through CHAMP1 haploinsufficiency and mutations are acting through dominant negative or gain of function mechanisms, leading to a more severe clinical phenotype. Understanding this pathogenesis is important to the future of novel therapies for CHAMP1 disorder and illustrates that mechanistic understanding of mutations must be carefully considered prior to treatment development.

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CHAMP1 disorder is associated with a complex neurobehavioral phenotype including autism, ADHD, repetitive behaviors and sensory symptoms

Cited by 11 publications

References 45 publications

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

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

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations do not act through haploinsufficiency

Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency

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