• classic dopamine transporter deficiency syndrome

This report describes infantile parkinsonism-dystonia (PKDYS); PKDYS exhibits autosomal recessive inheritance. The human gene implicated in this disease is SLC6A3, which encodes a dopamine transporter that effects reuptake of the neurotransmitter at presynaptic terminals (a sodium:neurotransmitter symporter). There is a single orthologous dopamine transporter in Drosophila, DAT, for which classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\DAT is also orthologous to second gene in human, SLC6A2, which acts as a sodium:neurotransmitter symporter for norepinephrine in human. The role of SLC6A3 in development of ADHD and autism has also been investigated in flies (see FBhh0000654 and FBhh0000652).

Multiple different UAS constructs of the human Hsap\SLC6A3 gene have been introduced into flies, including wild-type SLC6A3 and genes carrying mutational lesions. Heterologous rescue (functional complementation) is observed: expression of wild-type SLC6A3 in dopaminergic neurons is able to rescue the hyperactive phenotype of a Dmel\DAT loss-of-function allele. Variant(s) implicated in human disease tested (as transgenic human gene, SLC6A3): the R85L, V158F, L224P, G327R, L368Q, and P554L variant forms have been introduced into flies; these variants are implicated (or possibly implicated) in PKDYS.

Phenotypes of the original loss-of-function mutation of Dmel\DAT (DAT^fmn) include hyperactivity, sleep-defective phenotypes and locomotor-behavior-defective phenotypes. In this DAT mutant background, variant forms of the human gene fail to rescue the hyperactivity and sleep-defective phenotypes. The ability of pharmacological interventions to rescue phenotypes of the variant forms has been assessed; results differ for the different variants, as do lethal or detrimental effects of drug administration.

[updated Mar. 2020 by FlyBase; FBrf0222196]