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

Abstract

Tyrosine hydroxylase (TH) enzyme is a rate limiting enzyme in dopamine biosynthesis. Missense mutation in both alleles of the TH gene is known to cause dopamine-related phenotypes, including dystonia and infantile Parkinsonism. However, it is not clear if single allele mutation in TH modifies the susceptibility to the adult form of Parkinson disease (PD). We reported a novel deletion of entire TH gene in an adult with PD. The deletion was first identified by copy number variation (CNV) analysis in a genome-wide association study using Illumina Infinium BeadChips. After screening 635 cases and 642 controls, the deletion was found in one PD case but not in any control. The deletion was confirmed by multiple quantitative PCR (qPCR) assays. There is no additional exonic single nucleotide variant in the one copy of TH gene of the patient. The patient has an age-at-onset of 54 years, no evidence for dystonia, and was responsive to L-DOPA. This case supports the importance of the TH gene in PD pathogenesis and raises more attention to rare variants in candidate genes being a risk factor for Parkinson disease.

Figure 1

A heterozygous deletion over TH identified by SNP array. SNP array data were processed using Illumina BeadStudio software using NCBI36/Hg18 as the reference genome. The region shown is indicated by the red box on chromosome 11p15.4. A hemizygous deletion over TH is evident by lower log R ratio and a loss of heterozygotes in the B allele frequency. The seven SNPs that defined the deletion are indicated by the red circle.

Figure 2

qPCR confirmation of the deletion over TH. The hemizygous deletion (red horizontal bar) delimited by PennCNV and the custom designed CNV probes A-G, shown above, displayed on UCSC (Kent et al., 2002) genome browser (NCBI36/Hg18, Figure 2a); Taqman® CNV assay results in the patient and two controls samples (Figure 2b).