PUBLICATION
Loss of δ-catenin function in severe autism
- Authors
- Turner, T.N., Sharma, K., Oh, E.C., Liu, Y.P., Collins, R.L., Sosa, M.X., Auer, D.R., Brand, H., Sanders, S.J., Moreno-De-Luca, D., Pihur, V., Plona, T., Pike, K., Soppet, D.R., Smith, M.W., Cheung, S.W., Martin, C.L., State, M.W., Talkowski, M.E., Cook, E., Huganir, R., Katsanis, N., Chakravarti, A.
- ID
- ZDB-PUB-150326-2
- Date
- 2015
- Source
- Nature 520(7545): 51-6 (Journal)
- Registered Authors
- Katsanis, Nicholas
- Keywords
- none
- MeSH Terms
-
- Animals
- Autistic Disorder/genetics*
- Autistic Disorder/metabolism*
- Brain/embryology
- Brain/metabolism*
- Catenins/deficiency*
- Catenins/genetics*
- Catenins/metabolism
- Cells, Cultured
- Chromatin/genetics
- Chromatin/metabolism
- DNA Copy Number Variations/genetics
- Embryo, Mammalian/cytology
- Embryo, Mammalian/metabolism
- Exome/genetics
- Female
- Gene Expression
- Gene Expression Regulation, Developmental
- Hippocampus/pathology
- Humans
- Male
- Mice
- Models, Genetic
- Multifactorial Inheritance/genetics
- Mutation, Missense
- Nerve Net
- Neurons/cytology
- Neurons/metabolism
- Sex Characteristics
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 25807484 Full text @ Nature
Citation
Turner, T.N., Sharma, K., Oh, E.C., Liu, Y.P., Collins, R.L., Sosa, M.X., Auer, D.R., Brand, H., Sanders, S.J., Moreno-De-Luca, D., Pihur, V., Plona, T., Pike, K., Soppet, D.R., Smith, M.W., Cheung, S.W., Martin, C.L., State, M.W., Talkowski, M.E., Cook, E., Huganir, R., Katsanis, N., Chakravarti, A. (2015) Loss of δ-catenin function in severe autism. Nature. 520(7545):51-6.
Abstract
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping