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The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders
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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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“Later pregnancy and early postnatal life are additionally implicated by accumulating molecular and pathological evidence pointing to altered neuronal connectivity and a resultant perturbation in signaling pathways, systems under intense development in these periods.25,26”
From Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence (2014) · cites this paper as [26]
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“Evidence supporting environmental contributions to ASD risk include observations of incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation, whereby a significant percentage of carriers do not express autistic phenotypes [ 14 , 19 , 22 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [19]
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Self-citationAutism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks
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“We refer the reader to other networks and paradigms gaining traction (Bill and Geschwind, 2009; Ehninger et al, 2008b; Levitt and Campbell, 2009; Ramocki and Zoghbi, 2008; Sudhof, 2008), as we expect that multiple avenues will need to be pursued given the heterogeneity of ASD.”
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“Furthermore, many mutations associated with ASDs converge on the ERK pathway impairing cognitive functioning and adaptive behavioral plasticity (Komiyama et al., 2002; Levitt and Campbell, 2009; Ebert and Greenberg, 2013).”
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“…regulation is also abnormal in a large subgroup of autistic individuals (Samaco et al., 2005; Moretti and Zoghbi, 2006; Nagarajan et al., 2008; Levitt and Campbell, 2009; Ramocki et al., 2009), our studies may implicate a novel mechanism for autism where mitochondrial dysfunction also plays a…”
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“…pallidus, obscurus, magnus, and pontis) projecting to the spinal cord and the cerebellum, and the rostral division [B5–B9; including the dorsal (B6, B7) and median raphe nuclei (B5, B8)] projecting to the forebrain (Lidov and Molliver, 1982; Steinbusch and Nieuwenhuys, 1983; Törk, 1990; Figure 1A).”
Minireview: Targeting GPCR Activated ERK Pathways for Drug Discovery
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“Given that there is often a strong hereditary component in neuropsychiatric diseases, disorders in ERK pathway have been studied from this perspective [66, 67].”
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“Several of these mutations occurred in genes that were also found to play an important role in the development of the nervous system and taught us important lessons on possible mechanisms of brain function(Grice and Buxbaum, 2006; Kumar and Christian, 2009; Levitt and Campbell, 2009).”
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“The mTOR pathway has been shown to be an important signaling hub involved in autism spectrum disorders.(36) Following their migration to specific cortical layers, pyramidal neurons progressively develop a dendritic arborization and receive synaptic inputs.”
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“Moreover, there is incomplete concordance of ASD diagnosis in monozygotic twins [16], and even in genetic syndromes strongly associated with ASD, a significant percentage of carriers do not express autistic phenotypes [16,17].”
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“…appears to be an enrichment of ASD risk genes related to growth factor signaling (Wittkowski et al., 2014), aberrant ASD brain growth trajectories (Levitt and Campbell, 2009; Berg and Geschwind, 2012), and the coalescence of functional ASD gene networks in circuits involving superficial and deep…”
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Rapamycin improves sociability in the BTBR T+Itpr3/J mouse model of autism spectrum disorders
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BackgroundPlasma antioxidant capacity is reduced in Asperger syndrome
Parellada, M., Moreno, C., MacDowell, K. S., Leza, J. C., Giráldez, M., Bailón, C., Castro, C., Miranda-Azpiazu, P., Fraguas, D., & Arango, C. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2011.10.004 · Cited by 68
The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis
Tomita, H., Cornejo, F., Aranda-Pino, B., Woodard, C. L., Rioseco, C. C., Neel, B. G., Alvarez, A. R., Kaplan, D. R., Miller, F. D., & Cancino, G. I. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.11.033 · Cited by 64
“Genetic alterations in genes encoding components of these pathways are associated with abnormal development of the human CNS and have been implicated in human neurodevelopmental disorders (Ferguson, 2003; Schubbert et al., 2007; Levitt and Campbell, 2009; Samuels et al., 2009).”
BackgroundSheng, L., Ding, X., Ferguson, M., McCallister, M., Rhoades, R., Maguire, M., Ramesh, A., Aschner, M., Campbell, D., Levitt, P., et al. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq304 · Cited by 63
“Based on recent biological studies, we have suggested that MET receptor activation influences the development and maturation of these circuits (Levitt and Campbell, 2009).”
BackgroundSelf-citationThe Neurodevelopmental Implications of PI3K Signaling
Waite, K., & Eickholt, B. J. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_82 · Cited by 65
“Consequently, subtle aberrations in this signaling pathway are likely to underlie the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism (Kalkman 2006; Levitt and Campbell 2009).”
BackgroundMouse Models of Autism: Testing Hypotheses About Molecular Mechanisms
Roullet, F., & Crawley, J. N. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2010_113 · Cited by 67
“Rather, a variety of de novo and familial mutations have been documented, including a large number of genetic mutations and copy number variants, each in a small number of autistic individuals (Abrahams and Geschwind 2008; Cook and Scherer 2008; Levitt and Campbell 2009; Lintas and Persico 2009).”
BackgroundGross, C., & Bassell, G. J. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00012 · Cited by 63
“…not surprising that an increasing body of evidence suggests dysregulated PI3K activity and downstream signaling as a key contributor and potential therapeutic target for mental disorders (Kalkman, 2006; Levitt and Campbell, 2009; Karam et al., 2010; Waite and Eickholt, 2010; Krueger et al., 2013).”
Heuer, L., Braunschweig, D., Ashwood, P., Van de Water, J., & Campbell, D. B. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.48 · Cited by 62
Self-citationMarcogliese, P. C., Deal, S. L., Andrews, J. C., Harnish, J. M., Bhavana, V. H., Graves, H. K., Jangam, S. V., Luo, X., Liu, N., Bei, D., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110517 · Cited by 61
“Loss-or gain-of-function alleles in GLRA2 cause X-linked neurodevelopmental disorders Many genes implicated in ASD are also associated with neuro-developmental disorders beyond autism (Levitt and Campbell, 2009; Sullivan and Geschwind, 2019).”
DNA methylation, the early-life social environment and behavioral disorders
Szyf, M. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9079-2 · Cited by 63
“Several of these genes were also found to play an important role in the development of the nervous system and taught us important lessons on possible mechanisms of brain function (Grice and Buxbaum 2006; Kumar and Christian 2009; Levitt and Campbell 2009).”
BackgroundZhang, L., Bartley, C. M., Gong, X., Hsieh, L. S., Lin, T. V., Feliciano, D. M., & Bordey, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.09.009 · Cited by 62
“It also suggests that normalizing FLNA may be of benefit in other disorders where the MEK1-ERK1/ 2 pathway is hyperactive, such as autism spectrum disorders (Cuscó et al., 2009; Levitt and Campbell, 2009; Samuels et al., 2009).”
Ragusa, M., Santagati, M., Mirabella, F., Lauretta, G., Cirnigliaro, M., Brex, D., Barbagallo, C., Domini, C., Gulisano, M., Barone, R. M. E., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176203 · Cited by 61
Felice, A. D., Scattoni, M. L., Ricceri, L., & Calamandrei, G. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121663 · Cited by 61
“Unlike transgenic knockout mouse models, whose altered phenotype may be causally related to diminished or absent expression of single major genes, the impaired sociability of BTBR mice may reflect subtle epistatic interactions within a network of related genes, many of which may be normal polymorphisms [27, 28].”
BackgroundAutism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway
Lahiri, D. K., Sokol, D. K., Erickson, C. A., Ray, B., Ho, C. Y., & Maloney, B. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00094 · Cited by 63
Sanders, A. R., Drigalenko, E. I., Duan, J., Moy, W., Freda, J., Göring, H. H. H., Gejman, P. V., & on behalf of, M. G. S. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.47 · Cited by 57
Variations of plasma leptin and adiponectin levels in autistic patients
Blardi, P., Lalla, A. D., Ceccatelli, L., Vanessa, G., Auteri, A., & Hayek, J. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.05.027 · Cited by 55
Anterior insular cortex regulation in autism spectrum disorders
Carìa, A., & de Falco, S. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00038 · Cited by 60
Blood biomarker discovery for autism spectrum disorder: A proteomic analysis
Hewitson, L. C., Mathews, J. A., Devlin, M., Schutte, C., Lee, J., & German, D. C. (2021) · PLoS ONE · doi:10.1371/journal.pone.0246581 · Cited by 51
“The MAPK pathway is important in neural development, learning, and memory in syndromic conditions associated with ASD, such as tuberous sclerosis and Smith-Lemli-Opitz disorder [51].”
BackgroundRetractedGABRB2, a key player in neuropsychiatric disorders and beyond
Barki, M., & Xue, H. (2021) · Gene · doi:10.1016/j.gene.2021.146021 · Cited by 52
The autism risk genes MET and PLAUR differentially impact cortical development
Eagleson, K. L., Campbell, D. B., Thompson, B. L., Bergman, M. Y., & Levitt, P. R. (2010) · Autism Research · doi:10.1002/aur.172 · Cited by 52
“ASD is a highly heritable disorder that presents with heterogeneity in both the core triad of symptoms and co-occurring medical conditions [Geschwind, 2009; Jyonouchi, Geng, Ruby, & Zimmerman-Bier, 2005; Levitt & Campbell, 2009; Tuchman & Rapin, 2002; Valicenti-McDermott et al., 2006].”
BackgroundSelf-citationDoes microglial dysfunction play a role in autism and Rett syndrome?
Maezawa, I., Calafiore, M., Wulff, H., & Jin, L. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x1200004x · Cited by 53
“RTT is one of the ‘syndromic’ ASDs; these are a group of genetically diverse neurodevelopmental disorders with high penetrance of ASD diagnosis (Levitt and Campbell, 2009).”
BackgroundZuko, A., Bouyain, S., van der Zwaag, B., & Burbach, J. P. H. (2011) · Advances in protein chemistry and structural biology · doi:10.1016/b978-0-12-386483-3.00001-x · Cited by 54
NMDA receptor activation regulates sociability by its effect on mTOR signaling activity
Burket, J. A., Benson, A. D., Tang, A., & Deutsch, S. I. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.02.009 · Cited by 53
MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor
Peng, Y., Huentelman, M., Smith, C., & Qiu, S. (2013) · International Review of Neurobiology · doi:10.1016/b978-0-12-418700-9.00005-8 · Cited by 49
Campbell, D. B., Warren, D. E., Sutcliffe, J. S., Lee, E. B., & Levitt, P. R. (2009) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30998 · Cited by 49
Self-citationDiagnosis and Treatment of Neuropsychiatric Disorders
Taber, K. H., Hurley, R. A., & Yudofsky, S. C. (2010) · Annual Review of Medicine · doi:10.1146/annurev.med.051408.105018 · Cited by 50
A new synaptic player leading to autism risk: Met receptor tyrosine kinase
Judson, M. C., Eagleson, K. L., & Levitt, P. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-011-9081-8 · Cited by 43
“These genes encode proteins that are critical for MET receptor signaling (Levitt and Campbell 2009).”
BackgroundSelf-citationHoriuchi, M., Smith, L., Maezawa, I., & Jin, L. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.02.014 · Cited by 42
“RTT is one of few autistic diseases whose cause is identified as a single gene mutation and shares important pathogenic pathways with autism (Amir et al., 1999; Zoghbi, 2003; Levitt and Campbell, 2009; Chao et al., 2010; Gonzales, 2010).”
Yang, K., Cao, F., Sheikh, A. M., Malik, M. N., Wen, G. Y., Wei, H., Brown, W. T., & Li, X. (2012) · Brain Structure and Function · doi:10.1007/s00429-012-0420-7 · Cited by 43
“The function of these autism-linked genes converge on ERK signaling (Thomas et al. 2005; McKay and Morrison 2007; Chalhoub and Baker 2009; Levitt and Campbell 2009), which is consistent with a central role of ERK signaling in developmental regulation (Manning and Cantley 2007), social interaction…”
BackgroundSynaptic Dysfunction and Intellectual Disability
Valnegri, P., Sala, C., & Passafaro, M. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-3-7091-0932-8_19 · Cited by 44
Islam, F., Roy, S., Zehravi, M., Paul, S., Sutradhar, H., Yaidikar, L., Kumar, B., Dogiparthi, L. K., Prema, S., Nainu, F., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03706-z · Cited by 42
“This involves examining several key signaling pathways that may be affected by multiple genes and genetic variations, such as the ERK/MAPK pathway [111, 112].”
Russo, A. J. (2014) · Journal of Central Nervous System Disease · doi:10.4137/jcnsd.s13767 · Cited by 40
Pobbe, R. L. H., Pearson, B. L., Blanchard, D. C., & Blanchard, R. J. (2012) · Physiology & Behavior · doi:10.1016/j.physbeh.2012.02.024 · Cited by 40
Cheng, N., Alshammari, F., Hughes, E., Khanbabaei, M., & Rho, J. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0179409 · Cited by 42
Microglia and Brain Disorders: The Role of Vitamin D and Its Receptor
Mirarchi, A., Albi, E., Beccari, T., & Arcuri, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511892 · Cited by 47
“RTT is classified as a form of syndromic ASD [94].”
BackgroundRetinoic acid influences neuronal migration from the ganglionic eminence to the cerebral cortex
Crandall, J. E., Goodman, T. H., McCarthy, D. M., Duester, G., Bhide, P. G., Dräger, U. C., & McCaffery, P. J. A. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07471.x · Cited by 43
Rare deleterious mutations of the gene EFR3A in autism spectrum disorders
Gupta, A. R., Pirruccello, M., Cheng, F., Kang, H., Fernandez, T. V., Baskin, J. M., Choi, M., Liu, L., Ercan‐Sencicek, A. G., Murdoch, J. D., et al. (2014) · Molecular Autism · doi:10.1186/2040-2392-5-31 · Cited by 35
Metadata
- Authors
- Levitt, P., & Campbell, D. B.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Levitt, Pat
- ORCID
- Levitt, Pat
- Venue
- Journal of Clinical Investigation
- Published
- 2009-04-01
- Volume
- 119
- Issue
- 4
- Pages
- 747-754
- ISSN
- 0021-9738 (ISSN-L)
- 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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