Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (HDAT R51W) in dopamine neurotransmission and behaviors
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BACKGROUND: Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. METHODS: We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). OUTCOMES: Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. INTERPRETATION: We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.
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Two ASD-associated independent gene variants, including a gene variant regulating STX1 phosphorylation and dopamine transporter, that alter dopamine transporter function have been identified.
“Recently, two ASD associated independent gene variants, including a gene variants regulating STX1 phosphorylation (regulates neurotransmitter transporter) and dopamine transporter, that alter dopamine transporter function have been identified [188].”
From Vitamin D and Autism Spectrum Disorder: A Literature Review (2016) · cites this paper as [188]
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Yatham, L. N., & Malhi, G. S. (2011) · Oxford University Press eBooks · doi:10.1093/med/9780199562305.001.0001 · Cited by 3,515 · see citing works
Synaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Self-citationThe contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
Anderson, E. N. (1977) · Journal of California Anthropology, The · Cited by 2,550 · see citing works
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · see citing works
Self-citationSanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., Chu, S. H., Moreau, M. P., Gupta, A. R., Thomson, S. A., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.002 · Cited by 1,263 · see citing works
Self-citationDopamine in drug abuse and addiction: results from imaging studies and treatment implications
Volkow, N. D., Fowler, J. S., Wang, G.-J., & Swanson, J. M. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001507 · Cited by 1,101 · see citing works
SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation
Kristensen, A. S., Andersen, J., Jørgensen, T. N., Sørensen, L., Eriksen, J., Loland, C. J., Strømgaard, K., & Gether, U. (2011) · Pharmacological Reviews · doi:10.1124/pr.108.000869 · Cited by 865 · see citing works
Self-citation(1997) · PubMed · Cited by 645 · see citing works
Dopamine in Drug Abuse and Addiction: Results of Imaging Studies and Treatment Implications
Volkow, N. D., Fowler, J. S., Wang, G.-J., Swanson, J. M., & Telang, F. (2007) · Archives of Neurology · doi:10.1001/archneur.64.11.1575 · Cited by 605 · see citing works
Dopamine Is a Regulator of Arousal in the Fruit Fly
Kume, K., Kume, S., Park, S. K., Hirsh, J., & Jackson, F. R. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2048-05.2005 · Cited by 597 · see citing works
Prolonged dopamine signalling in striatum signals proximity and value of distant rewards
Howe, M. W., Tierney, P. L., Sandberg, S. G., Phillips, P. E. M., & Graybiel, A. M. (2013) · Nature · doi:10.1038/nature12475 · Cited by 565 · see citing works
Striatal Volume on Magnetic Resonance Imaging and Repetitive Behaviors in Autism
Hollander, E., Anagnostou, E. A., Chaplin, W. F., Esposito, K., Haznedar, M. M., LiCalzi, E. M., Wasserman, S., Soorya, L. V., & Buchsbaum, M. S. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.03.040 · Cited by 383 · see citing works
A role for casein kinase 2α in the Drosophila circadian clock
Lin, J.-M., Kilman, V. L., Keegan, K. P., Paddock, B. E., Emery-Le, M., Rosbash, M., & Allada, R. (2002) · Nature · doi:10.1038/nature01235 · Cited by 340 · see citing works
The role of dopamine in bipolar disorder
Cousins, D. A., Butts, K. A., & Young, A. H. (2009) · Bipolar Disorders · doi:10.1111/j.1399-5618.2009.00760.x · Cited by 286 · see citing works
Lim, E. T., Raychaudhuri, S., Sanders, S. J., Stevens, C., Sabo, A., MacArthur, D. G., Neale, B. M., Kirby, A., Ruderfer, D. M., Fromer, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.029 · Cited by 266 · see citing works
Self-citationChanges in the Developmental Trajectories of Striatum in Autism
Langen, M., Schnack, H. G., Nederveen, H., Bos, D. J., Lahuis, B., de Jonge, M. V., van Engeland, H., & Durston, S. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.03.017 · Cited by 257 · see citing works
Changes in the Development of Striatum Are Involved in Repetitive Behavior in Autism
Langen, M., Bos, D., Noordermeer, S. D. S., Nederveen, H., van Engeland, H., & Durston, S. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.08.013 · Cited by 256 · see citing works
Dopamine Transmission in the Human Striatum during Monetary Reward Tasks
Zald, D. H., Boileau, I., El-Dearedy, W., Gunn, R., McGlone, F., Dichter, G. S., & Dagher, A. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4643-03.2004 · Cited by 238 · see citing works
Reward circuitry function in autism during face anticipation and outcomes
Dichter, G. S., Richey, J. A., Rittenberg, A. M., Sabatino, A., & Bodfish, J. W. (2012) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-011-1221-1 · Cited by 222 · see citing works
Hamilton, P. J., Campbell, N. G., Sharma, S., Erreger, K., Herborg, F., Saunders, C., Belovich, A. N., Daly, M. J., Gibbs, R. A., Boerwinkle, E., et al. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.102 · Cited by 212 · see citing works
Self-citationCaudate Nucleus Is Enlarged in High-Functioning Medication-Naive Subjects with Autism
Langen, M., Durston, S., Staal, W., Palmen, S. J. M. C., & van Engeland, H. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.09.040 · Cited by 202 · see citing works
Hirling, H., & Scheller, R. H. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11945 · Cited by 182 · see citing works
Kohls, G., Perino, M. T., Taylor, J. M., Madva, E. N., Cayless, S. J., Troiani, V., Price, E., Faja, S., Herrington, J. D., & Schultz, R. T. (2013) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2013.07.020 · Cited by 170 · see citing works
Longitudinal patterns of repetitive behavior in toddlers with autism
Wolff, J. J., Botteron, K. N., Dager, S. R., Elison, J. T., Estes, A. M., Gu, H., Hazlett, H. C., Pandey, J., Paterson, S. J., Schultz, R. T., et al. (2014) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12207 · Cited by 170 · see citing works
Regulating the Conducting States of a Mammalian Serotonin Transporter
Quick, M. W. (2003) · Neuron · doi:10.1016/s0896-6273(03)00605-6 · Cited by 156 · see citing works
Liu, L., Sabo, A., Neale, B. M., Nagaswamy, U., Stevens, C., Lim, E., Bodea, C. A., Muzny, D., Reid, J. G., Banks, E., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003443 · Cited by 135 · see citing works
Self-citationSyntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux
Binda, F., Dipace, C., Bowton, E., Robertson, S. D., Lute, B. J., Fog, J. U., Zhang, M., Sen, N., Colbran, R. J., Gnegy, M. E., et al. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.048447 · Cited by 134 · see citing works
Self-citationBowton, E., Saunders, C., Reddy, I. A., Campbell, N. G., Hamilton, P. J., Henry, L. K., Coon, H. H., Sakrikar, D. S., Veenstra-VanderWeele, J. M., Blakely, R., et al. (2014) · Translational Psychiatry · doi:10.1038/tp.2014.90 · Cited by 124 · see citing works
Self-citationPIP2 regulates psychostimulant behaviors through its interaction with a membrane protein
Hamilton, P. J., Belovich, A. N., Khelashvili, G., Saunders, C., Erreger, K., Javitch, J. A., Sitte, H. H., Weinstein, H., Matthies, H. J. G., & Galli, A. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1545 · Cited by 122 · see citing works
Self-citationBowton, E., Saunders, C., Erreger, K., Sakrikar, D. S., Matthies, H. J. G., Sen, N., Jessen, T. N., Colbran, R. J., Caron, M. G., Javitch, J. A., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5094-09.2010 · Cited by 121 · see citing works
Self-citationHowe, M. W., Atallah, H. E., McCool, A. D., Gibson, D. J., & Graybiel, A. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113158108 · Cited by 116 · see citing works
Screening for autism spectrum disorders: state of the art in Europe
Primo, P. G., Hellendoorn, A., Charman, T., Roeyers, H., Dereu, M., Rogé, B., Baduel, S., Muratori, F., Narzisi, A., van Daalen, E., et al. (2014) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-014-0555-6 · Cited by 112 · see citing works
Insights into pathophysiology of punding reveal possible treatment strategies
Fasano, A. A., & Petrovic, I. (2010) · Molecular Psychiatry · doi:10.1038/mp.2009.95 · Cited by 100 · see citing works
Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD)
Nguyen, M., Roth, A., Kyzar, E. J., Poudel, M. K., Wong, K., Stewart, A., & Kalueff, A. V. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.01.002 · Cited by 95 · see citing works
Damiano, C. R., Aloi, J. M., Treadway, M. T., Bodfish, J. W., & Dichter, G. S. (2012) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-4-13 · Cited by 89 · see citing works
Phosphorylated Syntaxin 1 Is Localized to Discrete Domains Along a Subset of Axons
Foletti, D. L., Lin, R. C.-S., Finley, M., & Scheller, R. H. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-12-04535.2000 · Cited by 88 · see citing works
Nakamura, K., Anitha, A., Yamada, K., Tsujii, M., Iwayama, Y., Hattori, E., Toyota, T., Suda, S., Takei, N., Iwata, Y., et al. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145708009036 · Cited by 82 · see citing works
Impaired Learning of Social Compared to Monetary Rewards in Autism
Lin, A., Rangel, A., & Adolphs, R. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00143 · Cited by 79 · see citing works
Pizzo, A. B., Karam, C. S., Zhang, Y., Yano, H., Freyberg, R. J., Karam, D. S., Freyberg, Z., Yamamoto, A., McCabe, B. D., & Javitch, J. A. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.82 · Cited by 69 · see citing works
Hettinger, J. A., Liu, X., Hudson, M. L., Lee, A., Cohen, I. L., Michaelis, R. C., Schwartz, C. E., Lewis, S. M., & Holden, J. J. (2012) · Behavioral and Brain Functions · doi:10.1186/1744-9081-8-19 · Cited by 68 · see citing works
Dopamine release mediated by the dopamine transporter, facts and consequences
Leviel, V. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07335.x · Cited by 64 · see citing works
Role of syntaxin 1A on serotonin transporter expression in developing thalamocortical neurons
Quick, M. W. (2002) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(02)00021-7 · Cited by 64 · see citing works
Elevation of Dopamine D2 Receptors in Schizophrenia is Underestimated by Radioactive Raclopride
Seeman, P. M. (1990) · Archives of General Psychiatry · doi:10.1001/archpsyc.1990.01810240090014 · Cited by 63 · see citing works
Screening for Autism Spectrum Disorders in 12-Month-Old High-Risk Siblings by Parental Report
Rowberry, J., Macari, S. L., Chen, G., Campbell, D., Leventhal, J. M., Weitzman, C. C., & Chawarska, K. (2014) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-014-2211-x · Cited by 61 · see citing works
Dipace, C., Sung, U., Binda, F., Blakely, R., & Galli, A. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.026690 · Cited by 56 · see citing works
Self-citationDeficits in Syntaxin 1 Phosphorylation in Schizophrenia Prefrontal Cortex
Castillo, M. A., Ghose, S., Tamminga, C. A., & Ulery, P. G. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.029 · Cited by 54 · see citing works
Aksenova, M. V., Burbaeva, G. S., Kandror, K. V., et al. (1991) · FEBS Letters · doi:10.1016/0014-5793(91)80249-3 · Cited by 50 · see citing works
The Role of SNARE Proteins in Trafficking and Function of Neurotransmitter Transporters
Quick, M. W. (2006) · Springer eBooks · doi:10.1007/3-540-29784-7_9 · Cited by 50 · see citing works
Differentiating neural reward responsiveness in autism versus ADHD
Kohls, G., Thönessen, H., Bartley, G. K., Grossheinrich, N., Fink, G. R., Herpertz-Dahlmann, B., & Konrad, K. (2014) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2014.08.003 · Cited by 50 · see citing works
Subcellular localization of the antidepressant-sensitive norepinephrine transporter
Matthies, H. J. G., Han, Q., Shields, A. D., Wright, J., Moore, J. L., Winder, D. G., Galli, A., & Blakely, R. (2009) · BMC Neuroscience · doi:10.1186/1471-2202-10-65 · Cited by 43 · see citing works
Self-citationReplication study of Japanese cohorts supports the role of STX1A in autism susceptibility
Nakamura, K., Iwata, Y., Anitha, A., et al. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.11.033 · Cited by 41 · see citing works
Identification of syntaxin‐1A sites of phosphorylation by casein kinase I and casein kinase II
Dubois, T., Kerai, P., Learmonth, M., Cronshaw, A., & Aitken, A. (2002) · European Journal of Biochemistry · doi:10.1046/j.0014-2956.2001.02725.x · Cited by 35 · see citing works
Association between DRD4 genotype and Autistic Symptoms in DSM-IV ADHD.
Reiersen, A. M., & Todorov, A. A. (2011) · PubMed Central · Cited by 34 · see citing works
Drosophila CK2 regulates lateral-inhibition during eye and bristle development
Bose, A., Kahali, B., Zhang, S., et al. (2006) · Mechanisms of Development · doi:10.1016/j.mod.2006.07.003 · Cited by 32 · see citing works
Khelashvili, G., Galli, A., & Weinstein, H. (2012) · Biochemistry · doi:10.1021/bi300833z · Cited by 31 · see citing works
Self-citationGenetic variation in dopamine‐related gene expression influences motor skill learning in mice
Qian, Y., Chen, M., Forssberg, H., & Heijtz, R. D. (2013) · Genes, Brain and Behavior · doi:10.1111/gbb.12062 · Cited by 28 · see citing works
Rasmussen, T., Skjøth, I. H. E., Jensen, H. H., Niefind, K., Boldyreff, B., & Issinger, O. (2005) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-005-2944-0 · Cited by 23 · see citing works
STX1A and Asperger syndrome: a replication study
Durdiaková, J., Warrier, V., Banerjee‐Basu, S., et al. (2014) · Molecular Autism · doi:10.1186/2040-2392-5-14 · Cited by 23 · see citing works
Yoo, H. J., Cho, I. H., Park, M., Yang, S. Y., & Kim, S. A. (2013) · Journal of Korean Medical Science · doi:10.3346/jkms.2013.28.9.1403 · Cited by 15 · see citing works
Pizzo, A. B., Karam, C. S., Zhang, Y., Yamamoto, A., McCabe, B. D., & Javitch, J. A. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-800044-1.00052-0 · Cited by 2 · see citing works
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Vitamin D and Autism Spectrum Disorder: A Literature Review
Mazahery, H., Camargo, C., Conlon, C., Beck, K., Kruger, M., & Von Hurst, P. (2016) · Nutrients · doi:10.3390/nu8040236 · Cited by 110 · see citing works
- Authors
- Cartier, E., Hamilton, P. J., Belovich, A. N., Shekar, A., Campbell, N. G., Saunders, C., Andreassen, T. F., Gether, U., Veenstra-Vanderweele, J., Sutcliffe, J. S., Ulery-Reynolds, P. G., Erreger, K., Matthies, H. J. G., & Galli, A.
- Affiliations
- Vanderbilt University (US)
- University of Copenhagen (DK)
- New York State Psychiatric Institute (US)
- Corresponding author
- Erreger, Kevin
- Matthies, Heinrich J.G.
- Galli, Aurelio
- ORCID
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 2
- Issue
- 2
- Pages
- 135-146
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC4353922
- OpenAlex
- W2137284688
- Cited by
- 74
- References
- 61
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 10 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 13 · 2016: 7 · 2015: 4
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (0909667)
- Danmarks Frie Forskningsfond
- National Institutes of Health (DA012408)
- National Institute of Mental Health (R01MH094604)
- National Institute on Drug Abuse (P01DA012408, F31DA035535, R01DA038058)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, syntaxin-1, dopamine transporter, dopamine signaling, dopamine homeostasis, casein kinase 2, synaptic vesicle fusion, rare variants, animal models, dopamine reuptake
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