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

Source:http://linkedlifedata.com/resource/pubmed/id/19478460

Download in:

View as

General Info

Authors

Li Y, Reith ME, Heales SJ, Maher ER, Morgan NV, Gissen P, Jardine P, Tee L, Wassmer E, Zhen J, Meyer E, Pasha S, Cheng SY, Mordekar SR, Kurian MA

Affiliation

Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, United Kingdom.

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.

PMID
19478460

Publication types

Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural