RRC ID 59623
Author Wong WR, Brugman KI, Maher S, Oh JY, Howe K, Kato M, Sternberg PW.
Title Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.
Journal Hum Mol Genet
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.
Volume 28(13)
Pages 2271-2281
Published 2019-7-1
DOI 10.1093/hmg/ddz051
PII 5424048
PMID 31220273
PMC PMC6586145
MeSH Alleles Animals Autism Spectrum Disorder / genetics* CRISPR-Cas Systems Caenorhabditis elegans / genetics* Disease Models, Animal Fertility / genetics Genetic Association Studies Locomotion / genetics Mutation, Missense Neurodevelopmental Disorders / genetics Phenotype
IF 4.544
Times Cited 2
C.elegans tm6139