Submission Details

SLC6A3 (also known as DAT1) was first reported in association with SLC6A3-related dopamine transporter deficiency syndrome (previously Parkinsonism-dystonia, infantile, 1) in 2009 (Kurian et al., PMID:19478460). This complex neurological disorder is characterized by parkinsonism, dystonia, ocular flutter, rigidity, dyskinesia, and other neuromuscular phenotypes. Onset usually occurrs in the first year of life (classical DTDS), but the disease sometimes presents in childhood or adulthood (atypical DTDS). The severity of phenotypes increase over time, resulting in severe motor decline while cognitive function is relatively retained. The disease is most commonly identified by an increased ratio of homovanillic acid to 5-Hydroxyindoleacetic acid (HVA:HIAA) in the urine or cerebrospinal fluid, but many patients are misdiagnosed with cerebral palsy (PMID:19478460).

Eight variants (3 missense, 2 in-frame indels, 1 nonsense, 1 frameshift, and 1 splice site variant) that have been reported in 8 probands in 6 publications (PMIDs: 19478460, 34797406, 21112253, 24613933, 33015223, 32077500) are included in this curation. More evidence is available in the literature, but the maximum score of 12 pts for genetic evidence has been reached.

The mechanism of pathogenicity appears to be biallelic loss of function. 3 out of 8 variants included in this curation were located in or near the protein region designated as extracellular loop 4 (EL4) which appears to be a critical region for protein functioning. Through study of similar proteins, some have suggested that EL4 is important for the inward movement of the transmembrane regions (PMID:32077500). Overall, further studies are required to confirm the role of EL4 in DTDS.

This gene-disease relationship is also supported by biochemical evidence, expression evidence, animal models, and genetic rescues in mice and patient cells (PMIDs: 1948034 23715323, 12958210, 28972153, 34011628). Shimada et al. (2009) confirmed the biochemical function of the SLC6A3 gene product to be as a dopamine transporter by inserting the mRNA into Xenopus oocytes, which then showed 5x increased dopamine uptake (PMID:1948034). This is evidence for a relationship between SLC6A3 and dopamine transporter deficiency syndrome because lack of dopamine uptake would lead to increased HVA concentration, a hallmark phenotype for the disease. Additional biochemical evidence includes disruption of the SLC18A2 gene (which encodes a monoamine transporter) is implicated in a disease with a similar phenotype (infantile parkinsonism-dystonia 2) (PMID:23363473). Next, the GTEx database shows highly specific expression of SLC6A3 in the substantia nigra, which contains dopaminergic neurons. Degradation of this region of the brain is one of the most prominent physical features of Parkinson’s disease (PMID:15743669). In the fly model, replacement of the Drosophila ortholog of SLC6A3 with a human variant resulted in hyperlocomotion, a comparable phenotype to hyperkinetic movements seen in affected humans (PMID:28972153). Finally, the mouse model demonstrates disease features such as gait disturbance and motor dysfunction, as well as decreased DA uptake and increased HVA concentration (PMID:12958210). The phenotypes seen in these mice were rescued using a wild-type copy of human SLC6A3. The rescue resulted in the knockout mice being behaviorally indistinguishable from the wild-type mice, with improved DA and HVA levels. Finally, DA and HVA levels in patient induced pluripotent stem cells were improved using CRISPR insertion of a wild-type version of human SLC6A3 (PMID:34011628).

In summary, SLC6A3 is definitively associated with autosomal recessive SLC6A3-related dopamine transporter deficiency syndrome. This has been repeated in clinical and diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on the meeting date 09/09/2022 (SOP Version 9).