Cited by 234Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersWilliams Syndrome Research

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The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

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Levitt, Pat, Campbell, Daniel B.·2009·Journal of Clinical Investigation

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Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.

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Background
Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder
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Background
Effects of ω-3 fatty acids on stereotypical behavior and social interactions in Wistar rats prenatally exposed to lipopolysaccarides
Fortunato, J. J., da Rosa, N., Laurentino, A. O. M., da Silva, M. G., Michalak, C., Borges, L. P., Soares, E. D. C. C., Reis, P. A., Neto, H. C. D. C. F., & Petronilho, F. C. (2016) · Nutrition · doi:10.1016/j.nut.2016.10.019 · Cited by 38
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“The value of these data is enhanced by the diversification of methods and approaches used: APC [49] association study, [50]; PI3 kinases [51] review article, [42] CGH-microarray; Tsc1/2 [52]; SLIT1 [53] association study; ROBO3 and ROBO4 [54] association study; ROBO1 and ROBO2 [54] analysis of mRNA levels in lymphocyt…”
Method
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Self-citation
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Self-citation
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“Over the past decade, the contribution of genetics in ASD pathophysiology has been extensively established [7], with hundreds of diverse genetic polymorphisms linked to the disorder [8,9].”
Background
Maternal mid-gestational and child cord blood immune signatures are strongly associated with offspring risk of ASD
Che, X., Hornig, M., Bresnahan, M., Stoltenberg, C., Magnus, P. M., Surén, P., Mjaaland, S., Reichborn-Kjennerud, T., Susser, E., & Lipkin, W. I. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01415-4 · Cited by 33
“23, 69, 70 In summary, our results provide robust evidence of immune dysregulation in mothers as early as 17–21 weeks gestation and in CB of neonates later diagnosed with ASD.”
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Background
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“Gene expression levels were calculated and normalized to fragments per kilobase of transcript per million mapped reads (FPKM) using the RSEM software (version 1.2.12) (Li and Dewey, 2011) with default parameters.”
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Background
Time Reproduction Performance Is Associated With Age and Working Memory in High‐Functioning Youth With Autism Spectrum Disorder
Brenner, L. A., Shih, V. H., Colich, N. L., Sugar, C. A., Bearden, C. E., & Dapretto, M. (2014) · Autism Research · doi:10.1002/aur.1401 · Cited by 28
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Background
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Background
How do we establish a biological marker for a behaviorally defined disorder? Autism as a test case
Yerys, B. E., & Pennington, B. F. (2011) · Autism Research · doi:10.1002/aur.204 · Cited by 24
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Background
Recent Advances in the Pathogenesis of Syndromic Autisms
Benvenuto, A., Manzi, B., Alessandrelli, R., Galasso, C., & Curatolo, P. (2009) · International Journal of Pediatrics · doi:10.1155/2009/198736 · Cited by 24
“[83]”
Transcriptional Gene Silencing of the Autism-Associated Long Noncoding RNA MSNP1AS in Human Neural Progenitor Cells
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Self-citation
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BackgroundSelf-citation
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Gill, P. S., Clothier, J. L., Veerapandiyan, A., Dweep, H., Porter-Gill, P. A., & Schaefer, G. B. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11090848 · Cited by 22
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Background
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Background
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Background
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Yoon, S. Y., Kwon, S.-G., Kim, Y. H., Yeo, J., Ko, H., Roh, D., Kaang, B., Beitz, A. J., Lee, J., & Oh, S. B. (2017) · Molecular Pain · doi:10.1177/1744806916688902 · Cited by 21
“It has been reported that ERK signaling is disrupted in ASD, which results from a number of single gene mutations.(5,39) However, it is unknown whether the SIBs observed in ASD are in fact related to dysfunction of NMDA-ERK signaling.”
Background
A Clinically Relevant Selective ERK-Pathway Inhibitor Reverses Core Deficits in a Mouse Model of Autism
Murari, K., Abushaibah, A., Rho, J. M., Turner, R. W., & Cheng, N. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2023.104565 · Cited by 20
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Background
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Wu, W.-L., Cheng, S., Lin, S.-H., Chuang, Y.-C., Huang, E. Y., & Chen, C. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00086 · Cited by 18
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BackgroundInfluential
Receptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse
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Self-citation
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Schwartz, D. D., Katzenstein, J. M., Highley, E. J., Stabley, D. L., Sol‐Church, K., Gripp, K. W., & Axelrad, M. E. (2017) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.38174 · Cited by 18
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Self-citation
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Lein, P. J. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800228-5.00001-7 · Cited by 20
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Geng, R., Fang, S., & Li, G. (2019) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2019.05.003 · Cited by 17
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Background
Is the Risk of Autism in Younger Siblings of Affected Children Moderated by Sex, Race/Ethnicity, or Gestational Age?
Xie, F., Peltier, M. R., & Getahun, D. (2016) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0000000000000341 · Cited by 18
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“Given the overlap in behavioral phenotypes and possible genetic contributors of NF1 and ASD, including the Rat sarcoma (RAS)/Mitogen-Activated Protein Kinase (MAPK) pathway (Adviento et al., 2014; Levitt & Campbell, 2009), the comorbidity of ASD in NF1 is of interest.”

Authors: Levitt, P., & Campbell, D. B.
Affiliations: Vanderbilt University (US)
Corresponding author: Levitt, Pat
ORCID: Levitt, Pat
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2009-04-01
Volume: 119
Issue: 4
Pages: 747-754
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci37934
PMC: PMC2662567
OpenAlex: W2018736722
Cited by: 234
References: 115
Citations by year: 2026: 4 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 18 · 2016: 13 · 2015: 14 · 2014: 27 · 2013: 16 · 2012: 26
FWCI: 1.91
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
Keywords: autism spectrum disorder, genetic etiology, de novo mutations, common genetic variants, ERK signaling, PI3K signaling, receptor tyrosine kinase, neurodevelopmental syndrome, neurodevelopmental disorders
MeSH terms: Alleles, Autistic Disorder, Child, Female, Humans, Male, Models, Genetic, Models, Neurological, Mutation, Proto-Oncogene Proteins, Genetic Variation, Signal Transduction, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Genetic Predisposition to Disease, MAP Kinase Signaling System, Genome-Wide Association Study

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The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

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