title: Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).
abstract: Mutations in the parkin gene have been identified as a common cause of autosomal recessive inherited Parkinson disease (PD) associated with early disease manifestation. However, based on linkage data, mutations in other genes contribute to the genetic heterogeneity of early-onset PD (EOPD). Recently, two mutations in the DJ1 gene were described as a second cause of autosomal recessive EOPD (PARK7). Analyzing the PARK7/DJ1 gene in 104 EOPD patients, we identified a third mutation, c.192G>C (p.E64D), associated with EOPD in a patient of Turkish ancestry and characterized the functional significance of this amino acid substitution. In the patient, a substantial reduction of dopamine uptake transporter (DAT) binding was found in the striatum using [(18)F]FP-CIT and PET, indicating a serious loss of presynaptic dopaminergic afferents. His sister, homozygous for E64D, was clinically unaffected but showed reduced dopamine uptake when compared with a clinically unaffected brother, who is heterozygous for E64D. We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells. Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein.
authors.affiliation: Department of Medical Genetics, University of Tübingen, Tübingen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Hering
authors.forename: Karsten M
authors.initials: KM
authors.lastname: Strauss
authors.forename: Xiao
authors.initials: X
authors.lastname: Tao
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Dirk
authors.initials: D
authors.lastname: Woitalla
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mietz
authors.forename: Slobodanka
authors.initials: S
authors.lastname: Petrovic
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Schaible
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002460:Cell Line / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D049268:Positron-Emission Tomography; D011487:Protein Conformation; D000071617:Protein Deglycase DJ-1; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000096:biosynthesis; D014421:Turkey / Q000208:ethnology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D011993:Recombinant Fusion Proteins; C493214:SLC6A3 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D004298:Dopamine