Distribution, type, and origin of Parkin mutations: Review and case studies

• Published in: Movement disorders Vol. 19; no. 10; pp. 1146 - 1157
• Main Authors: Hedrich, Katja, Eskelson, Cordula, Wilmot, Beth, Marder, Karen, Harris, Juliette, Garrels, Jennifer, Meija-Santana, Helen, Vieregge, Peter, Jacobs, Helfried, Bressman, Susan B., Lang, Anthony E., Kann, Martin, Abbruzzese, Giovanni, Martinelli, Paolo, Schwinger, Eberhard, Ozelius, Laurie J., Pramstaller, Peter P., Klein, Christine, Kramer, Patricia
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2004; Wiley
• Subjects: Adult; Biological and medical sciences; break point analysis; Case-Control Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; distribution; DNA Mutational Analysis; Exons - genetics; Female; Gene Deletion; Gene Frequency - genetics; Haplotypes; Homozygote; Humans; linkage disequilibrium; Linkage Disequilibrium - genetics; Male; Medical sciences; Neurology; origin; Parkin; Parkinson Disease - genetics; Pedigree; Point Mutation - genetics; recurrent mutations; Tumors of the nervous system. Phacomatoses; Ubiquitin-Protein Ligases - genetics; Case study; Nervous system diseases; Mutation; Parkin
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.20234

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. © 2004 Movement Disorder Society