title: Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.
abstract: 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.
authors.affiliation: Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, United Kingdom.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Juan
authors.initials: J
authors.lastname: Zhen
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Santosh R
authors.initials: SR
authors.lastname: Mordekar
authors.forename: Philip
authors.initials: P
authors.lastname: Jardine
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Maarten E A
authors.initials: ME
authors.lastname: Reith
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: 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
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human