Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions
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The 16p11.2 BP4-BP5 deletion and duplication syndromes are associated with a complex spectrum of neurodevelopmental phenotypes that includes developmental delay and autism spectrum disorder, with a reciprocal effect on head circumference, brain structure and body mass index. Mouse models of the 16p11.2 copy number variant have recapitulated some of the patient phenotypes, while studies in flies and zebrafish have uncovered several candidate contributory genes within the region, as well as complex genetic interactions. We evaluated one of these loci, KCTD13, by modeling haploinsufficiency and complete knockout in mice. In contrast to the zebrafish model, and in agreement with recent data, we found normal brain structure in heterozygous and homozygous mutants. However, recapitulating previously observed genetic interactions, we discovered sex-specific brain volumetric alterations in double heterozygous Kctd13xMvp and Kctd13xLat mice. Behavioral testing revealed a significant deficit in novel object recognition, novel location recognition and social transmission of food preference in Kctd13 mutants. These phenotypes were concomitant with a reduction in density of mature spines in the hippocampus, but potentially independent of RhoA abundance, which was unperturbed postnatally in our mutants. Furthermore, transcriptome analyses from cortex and hippocampus highlighted the dysregulation of pathways important in neurodevelopment, the most significant of which was synaptic formation. Together, these data suggest that KCTD13 contributes to the neurocognitive aspects of patients with the BP4-BP5 deletion, likely through genetic interactions with other loci.
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Kctd13-deficient mice also display cognitive deficits in several memory tasks, raising the possibility that similar mechanisms may contribute to ID pathogenesis in 16p11.2 CNVs.
“Kctd13-deficient mice also display cognitive deficits in several memory tasks [83], raising the possibility that similar mechanisms may contribute to ID pathogenesis in 16p11.2 CNVs.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [83]
These findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice.
“However, these findings do not generalize to mice: two follow-up studies reported normal brain size in Kctd13-deficient mice [82, 83].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [83]
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16p11.2 Copy Number Variations and Neurodevelopmental Disorders
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- Authors
- Arbogast, T., Razaz, P., Ellegood, J., McKinstry, S. U., Erdin, S., Currall, B., Aneichyk, T., Lerch, J. P., Qiu, L. R., Rodriguiz, R. M., Henkelman, R. M., Talkowski, M. E., Wetsel, W. C., Golzio, C., & Katsanis, N.
- Affiliations
- Duke University (US)
- Harvard University (US)
- Hospital for Sick Children (CA)
- Inserm (FR)
- Corresponding author
- Katsanis, Nicholas
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-12-26
- Volume
- 28
- Issue
- 9
- Pages
- 1474-1486
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6489413
- OpenAlex
- W2906362256
- Cited by
- 52
- References
- 14
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 4 · 2020: 4 · 2019: 10
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Conte Center for Schizophrenia (P50 MH094268)
- National Institutes of Health (R01HD096326, R01NS093200)
- Simons Foundation (308955)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- 16p11.2 deletion, 16p11.2 duplication, copy number variation, short-term memory, novel object recognition, social transmission of food preference, synaptogenesis, brain development, autism spectrum disorder, MVP, LAT, haploinsufficiency, knockout mice
- MeSH terms
- Animals, Behavior, Animal, Disease Models, Animal, Female, Genotype, Male, Memory Disorders, Memory, Short-Term, Phenotype, Sex Factors, Gene Expression, Sequence Deletion, Mice, Knockout, Gene Targeting, Genetic Predisposition to Disease, Gene Expression Profiling, Ubiquitin-Protein Ligase Complexes, Mice, Genetic Loci, CA1 Region, Hippocampal, Genetic Association Studies
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