Distribution, type, and origin of Parkin mutations: review and case studies.
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.
Hedrich
Katja
K
Department of Neurology, University of Lübeck, Lübeck, Germany.
Eskelson
Cordula
C
Wilmot
Beth
B
Marder
Karen
K
Harris
Juliette
J
Garrels
Jennifer
J
Meija-Santana
Helen
H
Vieregge
Peter
P
Jacobs
Helfried
H
Bressman
Susan B
SB
Lang
Anthony E
AE
Kann
Martin
M
Abbruzzese
Giovanni
G
Martinelli
Paolo
P
Schwinger
Eberhard
E
Ozelius
Laurie J
LJ
Pramstaller
Peter P
PP
Klein
Christine
C
Kramer
Patricia
P
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*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein