Homozygous in‐frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family

Abstract

The human dopamine transporter (hDAT) participates in dopamine homeostasis by clearing dopamine from the extracellular space using secondary active transport. Dysregulation of hDAT has been reported to be associated with different neuropsychiatric disorders. Dopamine transporter deficiency syndrome (DTDS) is a complex disease caused by defects in dopamine uptake within the synaptic cleft and patients manifest parkinsonian features. The extracellular loops are crucial for DAT activity and defects in these regions disturb dopamine transport. In the present study, a 3.5‐year‐old female in a consanguineous Iranian family with an initial diagnosis of gait imbalance and speech delay has been identified. We utilized whole‐exome sequencing (WES) to identify the possible genetic defect(s). WES identified a novel homozygous in‐frame indel variant, c.1139_1150del; p.(Gly380_Lys384delinsGlu), in the SLC6A3 gene (NM_001044.4), as the most likely disease‐susceptibility variant. This variant is located in extracellular loop 4 (EL4) of the DAT protein. Our study highlights the role of extracellular loops and shows the EL4 of hDAT as a critical region for the protein activity. The identified variant in the EL4 region of DAT is predicted to compromise DAT function and may lead to DTDS in this case. However, complementary studies are required to confirm.

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

“…DTDS was first discovered in infants, who manifested abnormal motor development (resting tremor, muscle rigidity, slow dystonic limb movements, abnormal muscle contractions, difficulties in feeding and global developmental delay). So far, at least 14 non-synonymous exonic variants, 3 truncated exonic variants, 7 intronic (including splice site) variants and 1 in frame variant have been identified among DTDS patients ( Baga et al, 2020 ; Heidari, Razmara, Hosseinpour, Tavasoli, & Garshasbi, 2020 ; Kurian et al, 2009 ; Kurian et al, 2011 ; Kuster et al, 2018 ; Ng et al, 2014 ; Puffenberger et al, 2012 ; Yildiz, Pektas, Tokatli, & Haliloglu, 2017 ). All DTDS mutations ( Fig.…”

The dopamine transporter gene SLC6A3: multidisease risks

“…PD Dystonia at birth 27 (2020) M Italian 793C>A 5 [ 49 ] (in silico predicted) damaged function 13 p.G380_K384 delinsE 0 In silico predicted change in splicing/gene expression and possibly damaging impact on transport function by deletion in EL4 DTDS class., inf. PD Dystonia 0.17 ≥5.5 (2019) F Iraninan 1277_1288del 8: in-frame deletion of 12 bp [ 50 ] (in silico predicted) 14 Y343X (0) d ND d DTDS class., inf. PD Dystonia 0.33 > 3 (2020) M Iranian 1167C>G 7 [ 51 ] 15 Δ N336 0 AMPH-DA efflux e ↓; stabilization of a more open intracellular gate; conformational flexibility ↓; N336 flies display hyperlocomotion, grooming and anxiety ↑, and social interaction ↓ Autism spectrum disorder < 16 ≥16 (2019) M European 1146CAAG>G 7 [ 52 ] 16 (9) G327R 0 Surface hDAT ↓ 1117G>A 7 [ 46 ] Q439X 0 DTDS class., inf.…”

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease

“…The dominant-negative action of hDAT-K619N is particularly noteworthy because patient 1, to our knowledge, is the first example of a heterozygote carrier of a coding DAT variant with early-onset parkinsonism. To date, all previously described patients with DTDS have been either homozygous or compound heterozygous for disruptive variants in SLC6A3 ( 13 , 15 – 17 , 50 , 51 ). Thus, the current data might conceptually and mechanistically expand the allelic disease spectrum of DTDS from biallelic nonsynonymous variants to single susceptibility/disease alleles.…”