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.

Alterations in the common fragile site gene Parkin in ovarian and other cancers

“…However, in contrast to most other disease-causing genes, the majority of Parkin mutations consist primarily of exonic duplications and deletions. Alterations have been documented through the Parkin coding sequence, but the majority of them localize between exons 2 and 8 of Parkin Lu¨cking et al, 2000;Hedrich et al, 2001Hedrich et al, , 2002Hoenicka et al, 2002;Kann et al, 2002;Nichols et al, 2002;West et al, 2002).…”

“…To further investigate potential alterations in Parkin in ovarian cancer, we utilized a screening method developed by Hedrich et al (2001), which they employed to search for heterozygous and homozygous deletions of the Parkin gene in ARJP patients. This method allows for the screening of all 12 Parkin exons by means of realtime quantitative PCR (Hedrich et al, 2001) and for the identification of duplications and deletions that were potentially undetectable using conventional PCR.…”

“…Hd mapping was performed using the quantitative duplex PCR technique described by Hedrich et al (2001). Hedrich et al (2001) used real-time PCR to determine the gene dosage ratio of the Parkin gene as compared to the reference gene beta globin (HBB) in order to identify heterozygous deletions and/or duplica- Primers used in a study by Hattori et al (1998).…”

“…Hedrich et al (2001) used real-time PCR to determine the gene dosage ratio of the Parkin gene as compared to the reference gene beta globin (HBB) in order to identify heterozygous deletions and/or duplica- Primers used in a study by Hattori et al (1998). b Primers used in a study by Denison et al (2003) Alterations in the common fragile site SR Denison et al tions of whole exons of Parkin in a subset of ARJP patients.…”

“…Linkage studies of autosomal recessive juvenile Parkinson's (ARJP) patients and their families identified the gene Parkin as a potential target for mutation in these patients . Mutational analysis of ARJP patients has revealed the presence of various intragenic deletions/duplications and point mutations in Parkin Lu¨cking et al, 2000;Hedrich et al, 2001Hedrich et al, , 2002Hoenicka et al, 2002;Kann et al, 2002;Nichols et al, 2002;West et al, 2002). Subsequently, these mutations have been demonstrated to be responsible for the manifestation of juvenile, earlyonset, and sometimes late-onset Parkinson's disease (Imai et al, 2000;Tanaka et al, 2001;Kahns et al, 2002).…”