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Guanosine triphosphate cyclohydrolase 1 promoter deletion causes dopa‐responsive dystonia
Author(s) -
Theuns Jessie,
Crosiers David,
Debaene Luc,
Nuytemans Karen,
Meeus Bram,
Sleegers Kristel,
Goossens Dirk,
Corsmit Ellen,
Elinck Ellen,
Peeters Karin,
Mattheijssens Maria,
Pickut Barbara,
DelFavero Jurgen,
Engelborghs Sebastiaan,
De Deyn Peter Paul,
Cras Patrick,
Van Broeckhoven Christine
Publication year - 2012
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.25147
Subject(s) - genetics , dystonia , exon , biology , gene , gtp cyclohydrolase i , positional cloning , microbiology and biotechnology , biochemistry , neuroscience , locus (genetics) , tetrahydrobiopterin , enzyme , cofactor
Background: Autosomal dominant dopa‐responsive dystonia (AD‐DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene ( GCH1 ) mutations. Few families have been reported without mutations in GCH1 . Methods: Genome‐wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD‐DRD family was carried out. Results and Conclusion: In this study, we report on the identification and characterization of a novel 24‐kb deletion spanning exon 1 and the 5′ regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD‐DRD family. This large‐scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis. © 2012 Movement Disorder Society