title: The V81M variant of tyrosine hydroxylase is associated with more severe freezing of gait in Parkinson's disease.
abstract: BACKGROUND
  Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis.
  
  
  METHODS
  We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme.
  
  
  RESULTS
  PD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81M TH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co-substrate BH4.
  
  
  CONCLUSIONS
  The data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG.
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Izel
authors.initials: I
authors.lastname: Tekin
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Nurgul
authors.initials: N
authors.lastname: Carkaci-Salli
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Department of Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Mechelle M
authors.initials: MM
authors.lastname: Lewis
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Department of Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Department of Neurology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA; Departments of Radiology and Neurosurgery, Milton S. Hershey Medical Center, and Kinesiology, Pennsylvania State University, Hershey, PA, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. Electronic address: kvrana@psu.edu.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Vrana
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D010300:Parkinson Disease / Q000150:complications*; D020641:Polymorphism, Single Nucleotide; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
chemical_list: D014446:Tyrosine 3-Monooxygenase
keywords: Dopamine; Movement disorders; Norepinephrine; Polymorphism; SNP