title: Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease.
abstract: OBJECTIVE
  Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinson's disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin.
  
  
  METHODS
  Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function.
  
  
  RESULTS
  We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants.
  
  
  CONCLUSIONS
  Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Hoffman-Zacharska
authors.affiliation: Department of Neurology, Faculty of Health Science, Medical University of Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Koziorowski
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Micha
authors.initials: M
authors.lastname: Milewski
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Jaros Aw
authors.initials: JA
authors.lastname: Poznanski
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Jurek
authors.affiliation: Department of Neurology, Mayo Clinic Florida, Jacksonville, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Soto-Ortolaza
authors.affiliation: Department of Neurological and Psychiatric Nursing, Medical University, Gdansk, Poland.|Department of Neurology, St. Albert Hospital, Gdansk, Poland.
authors.forename: Jaros Aw S
authors.initials: JAS
authors.lastname: Awek
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Janik
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Jamrozik
authors.affiliation: Department of Neurology, Medical University of Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.affiliation: Department of Neurology, Medical University of Silesia, Katowice, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jasinska-Myga
authors.affiliation: Department of Neurology, Medical University of Silesia, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Opala
authors.affiliation: Department of Neurology, Collegium Medicum Jagiellonian University, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Krygowska-Wajs
authors.affiliation: Department of Neurology, Central Hospital of the Ministry of Interior and Administration, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Czyzewski
authors.affiliation: Neuropathology Laboratory, Mayo Clinic Florida, Jacksonville, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bal
authors.affiliation: Department of Neurology, Faculty of Health Science, Medical University of Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Genetic etiology; Missense mutations; Parkinson's disease; SNCA gene; α-Synuclein
references.citation: J Biol Chem. 2005 Mar 11;280(10):9595-603
references.pmid: 15615727
references.citation: J Neurosci. 2002 Oct 15;22(20):8797-807
references.pmid: 12388586
references.citation: Parkinsonism Relat Disord. 2010 Feb;16(2):79-84
references.pmid: 19846332
references.citation: J Biol Chem. 2011 Jun 17;286(24):21450-7
references.pmid: 21524999
references.citation: Mov Disord. 2013 Jun;28(6):811-3
references.pmid: 23457019
references.citation: Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S24-7
references.pmid: 22166445
references.citation: Mov Disord. 2009 Sep 15;24(12):1811-9
references.pmid: 19562770
references.citation: Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S66-70
references.pmid: 22166458
references.citation: J Biol Chem. 2004 May 21;279(21):21966-75
references.pmid: 15028717
references.citation: Neurology. 2013 Mar 12;80(11):1062-4
references.pmid: 23427326
references.citation: Neurology. 2001 Oct 23;57(8):1497-9
references.pmid: 11673599
references.citation: Acta Neuropathol. 2013 May;125(5):753-69
references.pmid: 23404372