TY - JOUR
T1 - Distribution, type and origin of Parkin mutations: Review and case studies
AU - Hedrich, Katja
AU - Eskelson, Cordula
AU - Wilmot, Beth
AU - Marder, Karen
AU - Harris, Juliette
AU - Garrels, Jennifer
AU - Meija-Santana, Helen
AU - Vieregge, Peter
AU - Jacobs, Helfried
AU - Bressman, Susan B.
AU - Lang, Anthony E.
AU - Kann, Martin
AU - Abbruzzese, Giovanni
AU - Martinelli, Paolo
AU - Schwinger, Eberhard
AU - Ozelius, Laurie J.
AU - Pramstaller, Peter P.
AU - Klein, Christine
AU - Kramer, Patricia
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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 359 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots a 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 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 mutation in Parkin, regardless of the mutation type.
AB - 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 359 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots a 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 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 mutation in Parkin, regardless of the mutation type.
UR - http://www.scopus.com/inward/record.url?scp=7244261867&partnerID=8YFLogxK
U2 - 10.1002/mds.20234
DO - 10.1002/mds.20234
M3 - Journal articles
C2 - 15390068
AN - SCOPUS:7244261867
SN - 0885-3185
VL - 19
SP - 1146
EP - 1157
JO - Movement Disorders
JF - Movement Disorders
IS - 10
ER -