GCH1 in early-onset Parkinson's disease
Date
2009
Authors
Cobb, S. A.
Wider, C.
Ross, O. A.
Mata, I. F.
Adler, C. H.
Rajput, A.
Rajput, A. H.
Wu, R. M.
Hauser, R.
Josephs, K. A.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Mutations in GTP-cyclohydrolase 1 (GCH1) cause autosomal dominant dopa-responsive dystonia (DRD), characterized by childhood-onset foot dystonia that later generalizes. DRD patients frequently present with associated Parkinsonism. Conversely, early-onset Parkinson's disease (EOPD) patients commonly display dystonia. Herein, we investigated the frequency of GCH1 mutations in a series of 53 familial EOPD patients (21 with dystonia) and screened them for mutations in PRKN, PINK1, and DJ-1. In addition, we examined a matched EOPD patient-control series for association of common variability at the GCH1 locus and EOPD susceptibility. No GCH1 coding change or copy-number abnormality was identified in familial EOPD patients. A novel 18-bp deletion was found in the proximal promoter (two patients, one control), which is expected to knock out two regulatory elements previously shown to regulate GCH1 transcription. No association was found between GCH1 variability and risk of EOPD. Fourteen (26.4%) familial EOPD patients had homozygous or compound heterozygous PRKN mutations. PRKN-positive patients were 10 years younger than PRKNnegative patients and had a twofold higher prevalence of dystonia. This study does not support a significant role for genetic variation at the GCH1 locus in EOPD. However, our results further highlight the relevance of PRKN screening in familial EOPD. © 2009 Movement Disorder Society.
Description
Keywords
cytosine, DJ 1 protein, gene product, guanine, guanosine triphosphate cyclohydrolase I, parkin, protein pink1, unclassified drug, adolescent, adult, article, controlled study, dystonia, female, gene deletion, gene duplication, gene frequency, gene locus, gene sequence, genetic variability, heterozygote, homozygote, human, major clinical study, male, mutation rate, onset age, Parkinson disease, priority journal, single nucleotide polymorphism, Adult, Age of Onset, Aged, Aged, 80 and over, DNA, DNA Mutational Analysis, European Continental Ancestry Group, Female, Gene Dosage, Gene Frequency, Genetic Variation, GTP Cyclohydrolase, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, North America, Oncogene Proteins, Parkinson Disease, Polymorphism, Single Nucleotide, Protein Kinases, Ubiquitin-Protein Ligases
Citation
Movement Disorders
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