title: 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.
authors.affiliation: University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics Miami, FL 33136, USA.
authors.forename: Güney
authors.initials: G
authors.lastname: Bademci
authors.forename: Todd L
authors.initials: TL
authors.lastname: Edwards
authors.forename: Andre L
authors.initials: AL
authors.lastname: Torres
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
mesh_terms: D017668:Age of Onset; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
chemical_list: D014446:Tyrosine 3-Monooxygenase
references.citation: Am J Hum Genet. 2009 Jan;84(1):35-43
references.pmid: 19118814
references.citation: Free Radic Biol Med. 1996;20(1):53-61
references.pmid: 8903679
references.citation: Mol Genet Metab. 2009 May;97(1):18-20
references.pmid: 19282209
references.citation: Nat Genet. 2008 Jun;40(6):695-701
references.pmid: 18509313
references.citation: Genome Res. 2007 Nov;17(11):1665-74
references.pmid: 17921354
references.citation: Mov Disord. 2010 Mar 15;25(4):447-51
references.pmid: 20108370
references.citation: Genome Res. 2002 Jun;12(6):996-1006
references.pmid: 12045153
references.citation: Ann Hum Genet. 2010 Mar;74(2):97-109
references.pmid: 20070850
references.citation: Eur J Neurol. 2006 Apr;13(4):385-90
references.pmid: 16643317
references.citation: Neurology. 2001 Jan 23;56(2):260-3
references.pmid: 11160968
references.citation: Mol Neurobiol. 1998 Jun;16(3):285-309
references.pmid: 9626667
references.citation: J Clin Epidemiol. 1998 Jun;51(6):517-23
references.pmid: 9636001
references.citation: Nat Genet. 2005 May;37(5):549-54
references.pmid: 15838508