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Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans

Wong, Wan-Rong and Brugman, Katherine I. and Maher, Shayda and Oh, Jun Young and Howe, Kevin and Kato, Mihoko and Sternberg, Paul W. (2019) Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans. Human Molecular Genetics, 28 (13). pp. 2271-2281. ISSN 0964-6906. https://resolver.caltech.edu/CaltechAUTHORS:20190624-075623572

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Abstract

Autism spectrum disorder (ASD) involves thousands of alleles in over 850 genes, but the current functional inference tools are not sufficient to predict phenotypic changes. As a result, the causal relationship of most of these genetic variants in the pathogenesis of ASD has not yet been demonstrated and an experimental method prioritizing missense alleles for further intensive analysis is crucial. For this purpose, we have designed a pipeline that uses Caenorhabditis elegans as a genetic model to screen for phenotype-changing missense alleles inferred from human ASD studies. We identified highly conserved human ASD-associated missense variants in their C. elegans orthologs, used a CRISPR/Cas9-mediated homology-directed knock-in strategy to generate missense mutants and analyzed their impact on behaviors and development via several broad-spectrum assays. All tested missense alleles were predicted to perturb protein function, but we found only 70% of them showed detectable phenotypic changes in morphology, locomotion or fecundity. Our findings indicate that certain missense variants in the C. elegans orthologs of human CACNA1D, CHD7, CHD8, CUL3, DLG4, GLRA2, NAA15, PTEN, SYNGAP1 and TPH2 impact neurodevelopment and movement functions, elevating these genes as candidates for future study into ASD. Our approach will help prioritize functionally important missense variants for detailed studies in vertebrate models and human cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/hmg/ddz051DOIArticle
ORCID:
AuthorORCID
Wong, Wan-Rong0000-0002-9757-8145
Brugman, Katherine I.0000-0003-2625-2903
Maher, Shayda0000-0002-1987-6104
Oh, Jun Young0000-0002-5158-9017
Howe, Kevin0000-0002-1751-9226
Kato, Mihoko0000-0003-3827-8879
Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© The Author(s) 2019. Published by Oxford University Press. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). Received: 06 November 2018; Revision Received: 27 February 2019; Accepted: 04 March 2019; Published: 01 April 2019.
Funders:
Funding AgencyGrant Number
Simons Foundation367560
NIH Predoctoral FellowshipT32GM007616
Subject Keywords:alleles, phenotype, autistic disorder, caenorhabditis elegans, fertility, genes, locomotion, models, genetic, missense mutation, tryptophanase, vertebrates, genetics, pten gene, nervous system development, autism spectrum disorder, inference, crispr
Issue or Number:13
Record Number:CaltechAUTHORS:20190624-075623572
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190624-075623572
Official Citation:Wan-Rong Wong, Katherine I Brugman, Shayda Maher, Jun Young Oh, Kevin Howe, Mihoko Kato, Paul W Sternberg, Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans, Human Molecular Genetics, Volume 28, Issue 13, 1 July 2019, Pages 2271–2281, https://doi.org/10.1093/hmg/ddz051
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96649
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Jun 2019 17:11
Last Modified:03 Oct 2019 21:24

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