De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.
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| Title: | De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. |
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| Authors: | Hamilton, P J, Campbell, N G, Sharma, S, Erreger, K, Herborg Hansen, F, Saunders, C, Belovich, A N, Daly, M J, Gibbs, R A, Boerwinkle, E, Buxbaum, J D, Cook, E H, Devlin, B, Lim, E T, Neale, B M, Roeder, K, Sabo, A, Schellenberg, G D, Stevens, C, Sutcliffe, J S |
| Source: | Molecular Psychiatry. Dec2013, Vol. 18 Issue 12, p1315-1323. 9p. |
| Subjects: | Dopamine, Autism spectrum disorders, Drosophila melanogaster, Central nervous system, Leucine |
| Abstract: | De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions. [ABSTRACT FROM AUTHOR] |
| Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 92036036 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Hamilton%2C+P+J%22">Hamilton, P J</searchLink><br /><searchLink fieldCode="AR" term="%22Campbell%2C+N+G%22">Campbell, N G</searchLink><br /><searchLink fieldCode="AR" term="%22Sharma%2C+S%22">Sharma, S</searchLink><br /><searchLink fieldCode="AR" term="%22Erreger%2C+K%22">Erreger, K</searchLink><br /><searchLink fieldCode="AR" term="%22Herborg+Hansen%2C+F%22">Herborg Hansen, F</searchLink><br /><searchLink fieldCode="AR" term="%22Saunders%2C+C%22">Saunders, C</searchLink><br /><searchLink fieldCode="AR" term="%22Belovich%2C+A+N%22">Belovich, A N</searchLink><br /><searchLink fieldCode="AR" term="%22Daly%2C+M+J%22">Daly, M J</searchLink><br /><searchLink fieldCode="AR" term="%22Gibbs%2C+R+A%22">Gibbs, R A</searchLink><br /><searchLink fieldCode="AR" term="%22Boerwinkle%2C+E%22">Boerwinkle, E</searchLink><br /><searchLink fieldCode="AR" term="%22Buxbaum%2C+J+D%22">Buxbaum, J D</searchLink><br /><searchLink fieldCode="AR" term="%22Cook%2C+E+H%22">Cook, E H</searchLink><br /><searchLink fieldCode="AR" term="%22Devlin%2C+B%22">Devlin, B</searchLink><br /><searchLink fieldCode="AR" term="%22Lim%2C+E+T%22">Lim, E T</searchLink><br /><searchLink fieldCode="AR" term="%22Neale%2C+B+M%22">Neale, B M</searchLink><br /><searchLink fieldCode="AR" term="%22Roeder%2C+K%22">Roeder, K</searchLink><br /><searchLink fieldCode="AR" term="%22Sabo%2C+A%22">Sabo, A</searchLink><br /><searchLink fieldCode="AR" term="%22Schellenberg%2C+G+D%22">Schellenberg, G D</searchLink><br /><searchLink fieldCode="AR" term="%22Stevens%2C+C%22">Stevens, C</searchLink><br /><searchLink fieldCode="AR" term="%22Sutcliffe%2C+J+S%22">Sutcliffe, J S</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Molecular+Psychiatry%22">Molecular Psychiatry</searchLink>. Dec2013, Vol. 18 Issue 12, p1315-1323. 9p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Dopamine%22">Dopamine</searchLink><br /><searchLink fieldCode="DE" term="%22Autism+spectrum+disorders%22">Autism spectrum disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Drosophila+melanogaster%22">Drosophila melanogaster</searchLink><br /><searchLink fieldCode="DE" term="%22Central+nervous+system%22">Central nervous system</searchLink><br /><searchLink fieldCode="DE" term="%22Leucine%22">Leucine</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=92036036 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/mp.2013.102 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: 1315 Subjects: – SubjectFull: Dopamine Type: general – SubjectFull: Autism spectrum disorders Type: general – SubjectFull: Drosophila melanogaster Type: general – SubjectFull: Central nervous system Type: general – SubjectFull: Leucine Type: general Titles: – TitleFull: De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Hamilton, P J – PersonEntity: Name: NameFull: Campbell, N G – PersonEntity: Name: NameFull: Sharma, S – PersonEntity: Name: NameFull: Erreger, K – PersonEntity: Name: NameFull: Herborg Hansen, F – PersonEntity: Name: NameFull: Saunders, C – PersonEntity: Name: NameFull: Belovich, A N – PersonEntity: Name: NameFull: Daly, M J – PersonEntity: Name: NameFull: Gibbs, R A – PersonEntity: Name: NameFull: Boerwinkle, E – PersonEntity: Name: NameFull: Buxbaum, J D – PersonEntity: Name: NameFull: Cook, E H – PersonEntity: Name: NameFull: Devlin, B – PersonEntity: Name: NameFull: Lim, E T – PersonEntity: Name: NameFull: Neale, B M – PersonEntity: Name: NameFull: Roeder, K – PersonEntity: Name: NameFull: Sabo, A – PersonEntity: Name: NameFull: Schellenberg, G D – PersonEntity: Name: NameFull: Stevens, C – PersonEntity: Name: NameFull: Sutcliffe, J S IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 12 Text: Dec2013 Type: published Y: 2013 Identifiers: – Type: issn-print Value: 13594184 Numbering: – Type: volume Value: 18 – Type: issue Value: 12 Titles: – TitleFull: Molecular Psychiatry Type: main |
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