title: Genomic instability in the PARK2 locus is associated with Parkinson's disease.
abstract: Parkinson's disease (PD) is a common neurodegenerative disorder affecting mostly elderly people, although there is a group of patients developing so-called early-onset PD (EOPD). Mutations in the PARK2 gene are a common cause of autosomal recessive EOPD. PARK2 belongs to the family of extremely large human genes which are often localised in genomic common fragile sites (CFSs) and exhibit gross instability. PARK2 is located in the centre of FRA6E, the third most mutation-susceptible CFS of the human genome. The gene encompasses a region of 1.3 Mbp and, among its mutations, large rearrangements of single or multiple exons account for around 50%. We performed an analysis of the PARK2 gene in a group of 344 PD patients with EOPD and classical form of the disease. Copy number changes were first identified using multiplex ligation probe amplification (MLPA), with their ranges characterised by array comparative genomic hybridisation (aCGH). Exact breakpoints were mapped using direct sequencing. Rearrangements were found in eight subjects, including five deletions and three duplications. Rearrangements were mostly non-recurrent and no repetitive sequences or extended homologies were identified in the regions flanking breakpoint junctions. However, in most cases, 1-3 bp microhomologies were present, strongly suggesting that microhomology-mediated mechanisms, specifically non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR), are predominantly involved in the rearrangement processes in this genomic region.
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211, Warsaw, Poland.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawińskiego 5a, 02-106, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Ambroziak
authors.affiliation: Department of Neurology, Faculty of Heath Science, Medical University of Warsaw, Kondratowicza 8, 03-242, Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Koziorowski
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211, Warsaw, Poland.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawińskiego 5a, 02-106, Warsaw, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Duszyc
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawińskiego 5a, 02-106, Warsaw, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Górka-Skoczylas
authors.affiliation: Department of Neurology, Medical University of Warsaw, Banacha 1, 02-097, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Potulska-Chromik
authors.affiliation: Department of Neurological and Psychiatric Nursing, Medical University of Gdańsk, Dębinki 7, 80-952, Gdańsk, Poland.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sławek
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211, Warsaw, Poland. dhoffman@wp.pl.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawińskiego 5a, 02-106, Warsaw, Poland. dhoffman@wp.pl.
authors.forename: Dorota
authors.initials: D
authors.lastname: Hoffman-Zacharska
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D020440:Gene Duplication; D015321:Gene Rearrangement; D042822:Genomic Instability; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D011044:Poland; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Common fragile sites; FRA6E; Genomic rearrangements; PARK2; Parkinson’s disease
references.citation: Hum Mutat. 2000;15(1):7-12
references.pmid: 10612815
references.citation: N Engl J Med. 2000 May 25;342(21):1560-7
references.pmid: 10824074
references.citation: Neurosci Lett. 2006 May 29;400(1-2):44-7
references.pmid: 16517073
references.citation: Cancer Lett. 2006 Jan 28;232(1):48-57
references.pmid: 16221525
references.citation: Am J Hum Genet. 2005 Dec;77(6):966-87
references.pmid: 16380909
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18069-74
references.pmid: 16330769
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2005 Feb 5;133B(1):120-3
references.pmid: 15635662
references.citation: Eur J Biochem. 1999 Nov;265(3):849-61
references.pmid: 10518778
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):8921-7
references.pmid: 16709669
references.citation: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94
references.pmid: 17911161
references.citation: Hum Mutat. 2007 Dec;28(12):1236-40
references.pmid: 17676595
references.citation: Annu Rev Genet. 2007;41:169-92
references.pmid: 17608616
references.citation: Cell. 2007 Dec 28;131(7):1235-47
references.pmid: 18160035
references.citation: J Biol Chem. 2008 Jan 4;283(1):1-5
references.pmid: 17999957
references.citation: Biochim Biophys Acta. 2008 Jan;1779(1):3-16
references.pmid: 18078840
references.citation: Genome Res. 2008 Mar;18(3):370-9
references.pmid: 18230801
references.citation: Nat Genet. 2009 Jul;41(7):849-53
references.pmid: 19543269
references.citation: Parkinsonism Relat Disord. 2010 Feb;16(2):136-8
references.pmid: 19628420
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):75-89
references.pmid: 20598272
references.citation: Chromosoma. 2010 Dec;119(6):575-87
references.pmid: 20585795
references.citation: Cytogenet Genome Res. 2013;141(1):1-6
references.pmid: 23817294
references.citation: Parkinsonism Relat Disord. 2014 Jan;20 Suppl 1:S23-8
references.pmid: 24262182
references.citation: Parkinsonism Relat Disord. 2013 Nov;19(11):1057-60
references.pmid: 23916651
references.citation: Neurol Neurochir Pol. 2013 Jul-Aug;47(4):319-24
references.pmid: 23986421
references.citation: Int J Mol Sci. 2012;13(9):11974-99
references.pmid: 23109895
references.citation: Neurology. 2001 Oct 23;57(8):1497-9
references.pmid: 11673599
references.citation: Trends Genet. 2002 Feb;18(2):74-82
references.pmid: 11818139
references.citation: Genes Chromosomes Cancer. 2003 Sep;38(1):40-52
references.pmid: 12874785
references.citation: Cytogenet Genome Res. 2003;101(1):8-16
references.pmid: 14571130
references.citation: Oncogene. 2003 Nov 13;22(51):8370-8
references.pmid: 14614460
references.citation: Mov Disord. 2004 Oct;19(10):1146-57
references.pmid: 15390068
references.citation: CRC Crit Rev Biochem. 1985;19(2):89-106
references.pmid: 3905255
references.citation: Am J Hum Genet. 1987 Nov;41(5):882-90
references.pmid: 3674017
references.citation: Cancer Genet Cytogenet. 1989 Oct 15;42(2):157-71
references.pmid: 2551486
references.citation: Acta Neurol Scand. 1994 Apr;89(4):258-61
references.pmid: 8042442
references.citation: Mol Cell Biol. 1996 May;16(5):2164-73
references.pmid: 8628283
references.citation: Cell. 1997 Apr 18;89(2):215-25
references.pmid: 9108477
references.citation: Nature. 1998 Apr 9;392(6676):605-8
references.pmid: 9560156
references.citation: Mov Disord. 1998 Nov;13(6):885-94
references.pmid: 9827611
references.citation: Trends Genet. 1998 Dec;14(12):501-6
references.pmid: 9865156
references.citation: Recent Results Cancer Res. 1998;154:185-99
references.pmid: 10027000
references.citation: Neurogenetics. 2011 Nov;12(4):263-71
references.pmid: 21993715