Tyrosine hydroxylase gene: another piece of the genetic puzzle of Parkinson's disease

Abstract

The tyrosine hydroxylase (TH) gene encodes a monoxygenase that catalyzes the rate limiting step in dopamine biosynthesis. A hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. Consistent with the essential role of TH in dopamine homeostasis, missense mutations in both alleles of TH have been associated with severe Parkinsonism-related phenotypes including infantile Parkinsonism. It has been speculated for a long time that genetic variants in the TH gene modify adult-onset PD susceptibility but the answer has not been clear. Genetic variants (both sequence variations and structural variations) can be classified into three categories based on their relative frequency in population: common variants (polymorphisms), rare variants and mutations. Each of these factors has a different mode in influencing the genetic risk and often requires different approaches to decipher their contributions to the disease. In the past few years, the revolutionary advances in genomic technology have allowed systematic evaluations of these genetic variants in PD, such as the genome-wide association study (GWAS, to survey common variants), copy number variation analysis (to detect structural variations), and massive parallel next generation sequencing (to detect rare variants and mutations). In this review, we have summarized the latest evidence on TH genetic variants in PD, including our ongoing effort of using whole exome sequencing to search for rare variants in PD patients.

Fig. 1

Genomic variations in the TH gene. a) Display of the genomic variations in TH using the UCSC [50] genome browser (NCBI37/hg19). The “TH mutations” track displays the genomic position of disease causing missense, nonsense, frameshift and promoter region mutations as the vertical red line. The red horizontal bar displays the start and end position of the genomic deletions in TH reported by Bademci et al., 2010 and Ormazabal et al., 2011; b). Protein structure and missense/nonsense mutations in the TH protein. Point mutations are depicted with red arrows, phosphorylation sites of the serine residues activating the enzyme in the regulatory domain are depicted in blue ovals. The nomenclature of point mutation is based on the TH isoform 1 with 498 amino acids (NM_199292.2). Fig. (1b) is modified from Hufton et al. 1995[30]. (IBR=Intersubunit binding region)