Kctd13-deficient mice display short-term memory impairment and sex-dependent genetic interactions
| Autor: | Thomas Arbogast, Christelle Golzio, R. M. Henkelman, William C. Wetsel, Parisa Razaz, Benjamin Currall, Jacob Ellegood, Serkan Erdin, Lily R. Qiu, Ramona M. Rodriguiz, Spencer U. McKinstry, Jason P. Lerch, Michael E. Talkowski, Tanya Aneichyk, Nicholas Katsanis |
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| Přispěvatelé: | Duke University [Durham], Massachusetts General Hospital [Boston], The Hospital for sick children [Toronto] (SickKids), Duke University Medical Center, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte |
| Rok vydání: | 2018 |
| Předmět: |
Male
Genotype Gene Expression Hippocampus [SDV.GEN] Life Sciences [q-bio]/Genetics Biology Transcriptome Mice 03 medical and health sciences Sex Factors Gene interaction Gene duplication Genetics Animals Genetic Predisposition to Disease Copy-number variation CA1 Region Hippocampal Molecular Biology Zebrafish Genetic Association Studies Genetics (clinical) Sequence Deletion Mice Knockout Memory Disorders [SDV.GEN]Life Sciences [q-bio]/Genetics 0303 health sciences Behavior Animal Gene Expression Profiling 030305 genetics & heredity Ubiquitin-Protein Ligase Complexes General Medicine biology.organism_classification Phenotype Disease Models Animal Memory Short-Term Genetic Loci Gene Targeting Female General Article Haploinsufficiency |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, 2019, 28 (9), pp.1474-1486. ⟨10.1093/hmg/ddy436⟩ Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddy436 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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