Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia

Manju A Kurian, Juan Zhen, Shu-Yuan Cheng, Yan Li, Santosh R Mordekar, Philip Jardine, Neil V Morgan, Esther Meyer, Louise Tee, Shanaz Pasha, Evangeline Wassmer, Simon J R Heales, Paul Gissen, Maarten E A Reith, Eamonn R Maher

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1595-603
Number of pages9
JournalJournal of Clinical Investigation
Volume119
Issue number6
DOIs
Publication statusPublished - 26 May 2009

Keywords

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 5/genetics
  • Dopamine Plasma Membrane Transport Proteins/chemistry
  • Dystonia/genetics
  • Female
  • Homozygote
  • Humans
  • Male
  • Microsatellite Repeats/genetics
  • Molecular Sequence Data
  • Mutation/genetics
  • Oligonucleotide Array Sequence Analysis
  • Parkinsonian Disorders/genetics
  • Pedigree
  • Phenotype
  • Sequence Alignment
  • Sequence Homology, Amino Acid

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