Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease
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Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. / Herborg, Freja; Jensen, Kathrine L.; Tolstoy, Sasha; Arends, Natascha; Posselt, Leonie P.; Shekar, Aparna; Aguilar, Jenny; Lund, Viktor K.; Erreger, Kevin; Rickhag, Mattias; Lycas, Matthew D.; Lonsdale, Markus N.; Rahbek-Clemmensen, Troels; Sorensen, Andreas T.; Newman, Amy H.; Lokkegaard, Annemette; Kjaerulff, Ole; Werge, Thomas; Moller, Lisbeth B.; Matthies, Heinrich J. G.; Galli, Aurelio; Hjermind, Lena E.; Gether, Ulrik; IPSYCH Researchers.
In: JCI insight, Vol. 6, No. 18, 151496, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease
AU - Herborg, Freja
AU - Jensen, Kathrine L.
AU - Tolstoy, Sasha
AU - Arends, Natascha
AU - Posselt, Leonie P.
AU - Shekar, Aparna
AU - Aguilar, Jenny
AU - Lund, Viktor K.
AU - Erreger, Kevin
AU - Rickhag, Mattias
AU - Lycas, Matthew D.
AU - Lonsdale, Markus N.
AU - Rahbek-Clemmensen, Troels
AU - Sorensen, Andreas T.
AU - Newman, Amy H.
AU - Lokkegaard, Annemette
AU - Kjaerulff, Ole
AU - Werge, Thomas
AU - Moller, Lisbeth B.
AU - Matthies, Heinrich J. G.
AU - Galli, Aurelio
AU - Hjermind, Lena E.
AU - Gether, Ulrik
AU - IPSYCH Researchers
PY - 2021
Y1 - 2021
N2 - Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phenotypic spectrum of a DAT coding variant, DAT-K619N, which localizes to the critical C-terminal PSD-95/Discs-large/ZO-1 homology-binding motif of human DAT (hDAT). We identified the rare but recurrent hDAT-K619N variant in exome-sequenced samples of patients with neuropsychiatric diseases and a patient with early-onset neurodegenerative parkinsonism and comorbid neuropsychiatric disease. In cell cultures, hDAT-K619N displayed reduced uptake capacity, decreased surface expression, and accelerated turnover. Unilateral expression in mouse nigrostriatal neurons revealed differential effects of hDAT-K619N and hDATWT on dopamine-directed behaviors, and hDAT-K619N expression in Drosophila led to impairments in dopamine transmission with accompanying hyperlocomotion and age-dependent disturbances of the negative geotactic response. Moreover, cellular studies and viral expression of hDAT-K619N in mice demonstrated a dominant-negative effect of the hDAT-K619N mutant. Summarized, our results suggest that hDAT-K619N can effectuate dopamine dysfunction of pathological relevance in a dominant-negative manner.
AB - Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phenotypic spectrum of a DAT coding variant, DAT-K619N, which localizes to the critical C-terminal PSD-95/Discs-large/ZO-1 homology-binding motif of human DAT (hDAT). We identified the rare but recurrent hDAT-K619N variant in exome-sequenced samples of patients with neuropsychiatric diseases and a patient with early-onset neurodegenerative parkinsonism and comorbid neuropsychiatric disease. In cell cultures, hDAT-K619N displayed reduced uptake capacity, decreased surface expression, and accelerated turnover. Unilateral expression in mouse nigrostriatal neurons revealed differential effects of hDAT-K619N and hDATWT on dopamine-directed behaviors, and hDAT-K619N expression in Drosophila led to impairments in dopamine transmission with accompanying hyperlocomotion and age-dependent disturbances of the negative geotactic response. Moreover, cellular studies and viral expression of hDAT-K619N in mice demonstrated a dominant-negative effect of the hDAT-K619N mutant. Summarized, our results suggest that hDAT-K619N can effectuate dopamine dysfunction of pathological relevance in a dominant-negative manner.
KW - SEQUENCE VARIATION
KW - GENE
KW - AMPHETAMINE
KW - TRAFFICKING
KW - MICE
KW - NEUROTRANSMISSION
KW - OLIGOMERIZATION
KW - ARCHITECTURES
KW - HYPERACTIVITY
KW - MUTATIONS
U2 - 10.1172/jci.insight.151496
DO - 10.1172/jci.insight.151496
M3 - Journal article
C2 - 34375312
VL - 6
JO - JCI Insight
JF - JCI Insight
SN - 2379-3708
IS - 18
M1 - 151496
ER -
ID: 281594862