Abstract
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 hDAT-WT 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.
Highlights
Dopamine (DA) exerts strong effects on human behavior by supporting motor initiation and exploration and through modulation of higher cognitive functions, such as reinforcement learning and motivation [1, 2]
Inheritance investigations showed that the human DAT (hDAT)-K619N allele was paternally transmitted to patient 1 (Figure 1B), but it is not known whether the father has neurological or neuropsychiatric symptoms or signs because he did not want to be examined
We have provided new insight into the link between dopamine transporter (DAT) dysfunction and human disease by employing a translational approach to investigate the rare coding variant hDAT-K619N, which we identified in an index patient with early-onset parkinsonism as well as in multiple patients with psychiatric disorders
Summary
Dopamine (DA) exerts strong effects on human behavior by supporting motor initiation and exploration and through modulation of higher cognitive functions, such as reinforcement learning and motivation [1, 2]. Classical DTDS presents in early infancy [14, 15]; later studies have described cases with childhood/adolescent disease onset [16], and we recently identified an adult patient with compound heterozygote missense mutations in SLC6A3 that only partially disrupt DAT function; this patient has an atypical form of DTDS with adult-onset of motor symptoms and comorbid neuropsychiatric disease [17] The identification of this patient adds to several reports of heterozygous carriers of coding variants in SLC6A3 who have been diagnosed with neuropsychiatric disease, including bipolar disorder, ADHD, and autism spectrum disorder SLC6A3 shows a high degree of conservation and is constrained against loss-of-function variants — supporting the notion that perturbations of DAT function may contribute to malfunctioning states that impose the negative selection against such variants [29]
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