title: Distribution, type, and origin of Parkin mutations: review and case studies.
abstract: Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.
authors.affiliation: Department of Neurology, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hedrich
authors.forename: Cordula
authors.initials: C
authors.lastname: Eskelson
authors.forename: Beth
authors.initials: B
authors.lastname: Wilmot
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: Juliette
authors.initials: J
authors.lastname: Harris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Garrels
authors.forename: Helen
authors.initials: H
authors.lastname: Meija-Santana
authors.forename: Peter
authors.initials: P
authors.lastname: Vieregge
authors.forename: Helfried
authors.initials: H
authors.lastname: Jacobs
authors.forename: Susan B
authors.initials: SB
authors.lastname: Bressman
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Kann
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbruzzese
authors.forename: Paolo
authors.initials: P
authors.lastname: Martinelli
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schwinger
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Patricia
authors.initials: P
authors.lastname: Kramer
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D044767:Ubiquitin-Protein Ligases; C111567:parkin protein