Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early‐onset Parkinson's Disease

Abstract

Autosomal recessive Parkinson's disease (PD) with early-onset may be caused by mutations in the parkin gene (PARK2). We have ascertained 87 Danish patients with an early-onset form of PD (age at onset < or =40 years, or < or =50 years if family history is positive) in a multicenter study in order to determine the frequency of PARK2 mutations. Analysis of the GTP cyclohydrolase I gene (GCH1) and the tyrosine hydroxylase gene (TH), mutated in dopa-responsive dystonia and juvenile PD, have also been included. Ten different PARK2 mutations were identified in 10 patients. Two of the patients (2.3%) were found to have homozygous or compound heterozygous mutations, and eight of the patients (9.2%) were found to be heterozygous. A mutation has been identified in 10.4% of the sporadic cases and in 15.0% of cases with a positive family history of PD. One patient was found to be heterozygous for both a PARK2 mutation and a missense mutation (A6T) in TH of unknown significance. It cannot be excluded that both mutations contribute to the phenotype. No other putative disease causing TH or GCH1 mutations were found. In conclusion, homozygous, or compound heterozygous PARK2 mutations, and mutations in GCH1 and TH, are rare even in a population of PD patients with early-onset of the disease.

A rare novel deletion of the tyrosine hydroxylase gene in Parkinson disease

“…The patient also has a heterozygous duplication of exon 11 in the parkin gene. An additive effect of the two mutations may account for developing PD at an early age-at-onset in this patient (Hertz et al, 2006). 3) Animal studies have shown that TH enzyme activity decreases by age.…”

“…The rate limiting step in dopamine biosynthesis is catalyzed by the enzyme encoded by the tyrosine hydroxylase ( TH ; MIM# 191290 ) gene (Haavik and Toska., 1998). Consistent with its essential role in dopamine homeostasis, homozygous missense mutations in TH have been associated with dopamine-related phenotypes, such as Segawa's syndrome, L-DOPA responsive infantile parkinsonism, and L-DOPA responsive dystonia (DRD) (Furukawa et al, 2001; Hertz et al, 2006). However, it is not clear whether a single allele mutation in TH would modify an individual's susceptibility to PD.…”

Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

“…Previous studies investigating the contribution of rare coding GCH1 variants in small cohorts of cases with Parkinson’s disease have reported negative results although these were insufficiently powered to draw conclusions (Bandmann et al , 1996 a ; Hertz et al , 2006; Cobb et al , 2009). An as-yet unpublished meta-analysis of existing genome-wide association study data has, however, identified GCH1 as a common low-risk locus (Singleton, personal communication), consistent with the hypothesis of a causal role for GCH1 in Parkinson’s disease.…”

Evaluation of PARKIN gene variants in West Bengal Parkinson’s disease patients

“…In our study, only six PD patients (4%) possessed PRKN mutation (Table 2), which is lower than that reported in several comparable studies, which report PRKN mutations to be present in between 10.4 and 18.0% of early-onset cases. [18][19][20][21] Five missense mutations identified in our patients are located in the important functional domain of Parkin, that is, one in UBL, another in UPD, two in RING1, whereas other in IBR region-thus likely to be involved in the impairment of Parkin Interestingly, none of the 300 chromosomes harbored the variants suggesting the potential role of these mutations, if any, in PD, require to be evaluated by functional analysis. The novel mutation (ex 5, GTT4ATT) is predicted to be 'possibly damaging' (PolyPhen, http://coot.embl.de/PolyPhen/; SNPs3D, Mutation taster) and the amino acid in this position is highly conserved through Macaca mulatta, Pan paniscus, Callithrix jacchus, Bos mutus, Sus scrofa, Rattus norvegicus and Canis familiaris.…”