De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder
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De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. / Hamilton, P J; Campbell, N G; Sharma, S; Erreger, K; Hansen, Freja Herborg; Saunders, C; Belovich, A N; NIH ARRA Autism Sequencing Consortium; Sahai, M A; Cook, E H; Gether, U; McHaourab, H S; Matthies, H J G; Sutcliffe, J S; Galli, A.
In: Molecular Psychiatry, Vol. 18, No. 12, 12.2013, p. 1315-23.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder
AU - Hamilton, P J
AU - Campbell, N G
AU - Sharma, S
AU - Erreger, K
AU - Hansen, Freja Herborg
AU - Saunders, C
AU - Belovich, A N
AU - NIH ARRA Autism Sequencing Consortium
AU - Sahai, M A
AU - Cook, E H
AU - Gether, U
AU - McHaourab, H S
AU - Matthies, H J G
AU - Sutcliffe, J S
AU - Galli, A
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Animals
KW - Child Development Disorders, Pervasive
KW - Child, Preschool
KW - Dopamine
KW - Dopamine Plasma Membrane Transport Proteins
KW - Dopaminergic Neurons
KW - Drosophila melanogaster
KW - Homeostasis
KW - Humans
KW - Male
KW - Motor Activity
KW - Mutation, Missense
KW - Risk Factors
U2 - 10.1038/mp.2013.102
DO - 10.1038/mp.2013.102
M3 - Journal article
C2 - 23979605
VL - 18
SP - 1315
EP - 1323
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 12
ER -
ID: 119178705