Low frequency of GCH1 and TH mutations in Parkinson's disease

• Background: The causes of Parkinson's disease (PD) are unknown in the majority of patients. TheGCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopaminesynthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1were found to be enriched in PD patients, indicating a role for the enzyme in theneurodegenerative process.Methods: To further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56.7 ± 12.0 years) and 230 controls. We further included the tyrosine hydroxylasegene TH, also known to cause DRD. Gene dose assessments were performed to screen for large copy number variants in a subset of 48 patients with early-onset PD.Results: No putatively pathogenic GCH1 mutations were found. The frequency of rare heterozygous variants in the TH gene was 0.69% (7/1018) in the patient group and 0.22% (1/460) in the control group (p = 0.45).Conclusions: Previous studies have found that coding variants in the GCH1 gene may be considered a risk factor for PD. Our study indicates that mutations in GCH1 are rare in late-onset PD. Several patients carried heterozygous variants in the TH gene that may affect protein function. Our study was not designed to determine with certainty if any of these variants play a role as risk factors for late-onset PD.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Parkinson's disease

Dopa-responsive dystonia

GTP-Cyclohydrolase 1

Tyrosine hydroxylase

tation

Sequencing

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