Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.
Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been linked to a variety of neuropsychiatric disorders, particularly attention deficit hyperactivity disorder. In addition, the homozygous Slc6a3 knockout mouse displays a hyperactivity phenotype. Here, we analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense SLC6A3 mutations (p.L368Q and p.P395L) in both families. Functional studies demonstrated that both mutations were loss-of-function mutations that severely reduced levels of mature (85-kDa) DAT while having a differential effect on the apparent binding affinity of dopamine. Thus, in humans, loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder. Identification of the molecular basis of IPD suggests SLC6A3 as a candidate susceptibility gene for other movement disorders associated with parkinsonism and/or dystonic features.
Kurian
Manju A
MA
Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, United Kingdom.
Zhen
Juan
J
Cheng
Shu-Yuan
SY
Li
Yan
Y
Mordekar
Santosh R
SR
Jardine
Philip
P
Morgan
Neil V
NV
Meyer
Esther
E
Tee
Louise
L
Pasha
Shanaz
S
Wassmer
Evangeline
E
Heales
Simon J R
SJ
Gissen
Paul
P
Reith
Maarten E A
ME
Maher
Eamonn R
ER
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004421:Dystonia / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human