Hedrich, K. et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov. Disord. 19, 1146-1157

Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Movement Disorders (Impact Factor: 5.68). 10/2004; 19(10):1146 - 1157. 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

15 Reads
  • Source
    • "identified, half of which are point mutations and the other half large gene rearrangements. However, it is still unknown if all the identified genetic changes are pathogenic (Hedrich et al. 2004). The PARK2 gene is located on chromosome 6, locus 6q25.2-q27 and encompasses a genomic region of 1.3 Mbp. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder affecting mostly elderly people, although there is a group of patients developing so-called early-onset PD (EOPD). Mutations in the PARK2 gene are a common cause of autosomal recessive EOPD. PARK2 belongs to the family of extremely large human genes which are often localised in genomic common fragile sites (CFSs) and exhibit gross instability. PARK2 is located in the centre of FRA6E, the third most mutation-susceptible CFS of the human genome. The gene encompasses a region of 1.3 Mbp and, among its mutations, large rearrangements of single or multiple exons account for around 50 %. We performed an analysis of the PARK2 gene in a group of 344 PD patients with EOPD and classical form of the disease. Copy number changes were first identified using multiplex ligation probe amplification (MLPA), with their ranges characterised by array comparative genomic hybridisation (aCGH). Exact breakpoints were mapped using direct sequencing. Rearrangements were found in eight subjects, including five deletions and three duplications. Rearrangements were mostly non-recurrent and no repetitive sequences or extended homologies were identified in the regions flanking breakpoint junctions. However, in most cases, 1-3 bp microhomologies were present, strongly suggesting that microhomology-mediated mechanisms, specifically non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR), are predominantly involved in the rearrangement processes in this genomic region.
    Full-text · Article · Apr 2015 · Journal of applied genetics
  • Source
    • "The types of mutations found in PARK2 are highly variable, such as point mutations, small deletions/insertions, and exonic rearrangement (either deletion or duplication), and have been reported in all exons of the gene.5 Notably, point mutations or small insertions/deletions, which are found in approximately 50% of Caucasian PD patients with PARK2 mutations, are infrequent in Asian populations.2,3,5,6,7,8,9,10,11 Although PARK2 mutations were initially found in patients with familial PD with an autosomal-recessive mode of inheritance, heterozygous mutations were also not uncommonly found in PD patients.1,2,3,12,13 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and Purpose There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage mutation of PARK2, rather than a point mutation or small insertion/deletion mutation, was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations. Methods We performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested. Results We identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls. Conclusions Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.
    Full-text · Article · Jul 2014 · Journal of Clinical Neurology
  • Source
    • "The locus is mapped to the telomeric region of the long-arm of chromosome 6. More than 100 mutations are associated with Parkin, ranging from point mutations and deletions to rearrangements and duplications.20,21 Clinically, affected families show parkinsonism similar to sporadic cases, except for the age of onset, which occurs from childhood to 40 years and is rarely seen in individuals over 50 years of age.22 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson's disease (PD). Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.
    Full-text · Article · Oct 2012
Show more