SLC6A3 – Dopamine Transporter Deficiency Syndrome

Dopamine transporter deficiency syndrome (DTDS; MONDO:0013150) is an autosomal recessive neurodevelopmental disorder characterized by infantile‐onset parkinsonism dystonia, hyperkinetic movements, gait imbalance, and delayed speech (HP:0001300, HP:0002487, HP:0002141, HP:0000750). It results from biallelic loss‐of‐function variants in SLC6A3, encoding the dopamine transporter (DAT), which clears synaptic dopamine.

In the landmark cohort (n=11), homozygous or compound heterozygous SLC6A3 variants were identified in all patients presenting in infancy with hyperkinesia, parkinsonism or mixed movement disorders ([PMID:21112253]). A subsequent series added 8 unrelated probands with similar early‐onset progressive parkinsonism dystonia ([PMID:24613933]). A recent consanguineous case report described a 3.5-year-old female with gait imbalance and speech delay carrying a novel homozygous in-frame indel, c.1139_1150del (p.Gly380_Lys384delinsGlu) ([PMID:32077500]). These 20 patients span at least 5 unrelated families, with segregation consistent with autosomal recessive inheritance.

Variants reported include 3 missense (c.1561C>T (p.Arg521Trp), c.671T>C (p.Leu224Pro), c.1156G>A (p.Gly386Arg)), 2 splice-site (c.1767+2T>C, c.1031+1G>A), 1 frameshift (c.684del (p.His228fs)), and 1 in-frame indel (c.1139_1150del (p.Gly380_Lys384delinsGlu)). No common founder alleles have been described, and allele frequencies are negligible in population databases.

Functional studies demonstrate complete loss of DAT uptake activity for all missense variants in heterologous cells and aberrant dopamine efflux in some mutants. Pharmacochaperone rescue in vitro restored folding and surface expression of select mutants. In a DAT-knockout mouse model, AAV-mediated DAT expression normalized striatal dopamine dynamics and rescued motor deficits, while a C. elegans model humanized with hDAT variants confirmed loss‐of‐function phenotypes ([PMID:28417953]; [PMID:27519790]).

No studies have refuted the role of SLC6A3 in DTDS. Experimental rescue across multiple systems and consistent genotype–phenotype correlations support a definitive gene–disease relationship.

Key Take-home: Biallelic SLC6A3 variants cause autosomal recessive DTDS, and functional data, including pharmacochaperone and gene therapy rescue, underscore the clinical utility of genetic testing for early diagnosis and potential therapeutic development.

References

• The Lancet. Neurology | 2011 | Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study. PMID:21112253
• Brain | 2014 | Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood. PMID:24613933
• Annals of human genetics | 2020 | Homozygous in-frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family. PMID:32077500
• Scientific reports | 2017 | Recombinant Adeno-Associated Virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome. PMID:28417953
• The European journal of neuroscience | 2017 | A Caenorhabditis elegans model to study dopamine transporter deficiency syndrome. PMID:27519790

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