Evaluation of PINK1 variants in Indian Parkinson's disease patients☆
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder [1]. The prevalence of PD varies significantly around the world [2]. There is evidence that genetic factors also play a major role in the etiology of some cases of PD. Approximately 5–10% of PD patients have a familial pattern of inheritance. To date twelve chromosomal loci (PARK1- PARK13; PARK1 and 4 are same) and nine underlying genes, including PTEN induced kinase 1 (PINK1) gene, have been implicated in PD [3].
PINK1 is a 581 amino acid protein, containing an N-terminal mitochondrial targeting sequence (MTS) and a conserved serine/threonine kinase domain (amino acids, 156–509) [4]. It is ubiquitously expressed in the human brain, and is considered to be neuroprotective as illustrated in PINK1 knock out drosophila and mammalian cellular models [5]. Protein phosphorylation is likely to play an important role in PD pathogenesis, and PINK1 may participate either by directly phosphorylating or binding key cellular proteins governing neuronal survival [5]. It has been reported that in PD, PINK1 protein localizes to 5–10% of the Lewy bodies in the brain [6]. PINK1 mutations account for early onset PD (EOPD) approximately 1–7% in Caucasians [7], [8], [9], [10], [11]; about 8.9% in Japanese [12] and 3.7% in patients of Chinese origin [13], but no study has been reported on Indian patients.
The coding sequence of PINK1 is spread over eight exons encompassing ∼18.8 kb of genomic DNA. Among the variant alleles of the gene, a common polymorphism (Ala340Thr) was examined for its association with PD and Thr340 allele was proposed to pose a risk factor among Chinese but not in Finnish & Caucasians [14], [15], [16], [17]. The difference in the reported observation could be due to overall genomic variation among the population groups studied. This study was undertaken to examine contribution of PINK1 variants in Indian PD patients, and to our knowledge it is the first report on molecular genetic studies on Indian PD using PINK1 as a candidate gene.
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Patients and controls
A total of 294 PD patients (age range 11–85 years) were recruited in this study with their written informed consent as per the guidelines of the Indian Council of Medical Research. Parkinson's disease (PD) patients were examined in the Movement Disorder Clinic, Bangur Institute of Neurosciences & Psychiatry, Kolkata, India. Among the patients, 88 were ≤40 years old at onset (age range 11–40 years; mean age of onset, 34 ± 5 years) and 206 were >40 years old at onset (age range 41–85 years; mean
Evaluation of PINK1 variants in PD patients
The 250 PD patients recruited in this study were initially screened for mutation in Parkin and G2019S mutation in LRRK2 gene. None of the individuals harbored any mutation in Parkin or G2019S mutation in LRRK2. On screening these patients for nucleotide variants in PINK1 gene, 15 changes were identified, which include three non-synonymous (Arg246Gln, Arg276Gln and Ala340Thr), four synonymous (Leu63Leu, Pro179Pro, Gly197Gly and Thr282Thr) changes and seven variants in introns (Table 1). Among
Discussion
In this study we report identification of one novel (Arg246Gln) and one reported (Arg276Gln) change in the PINK1 gene with the potential for association with the disease. These two non-synonymous changes, identified in five PD patients, represent 2% of the PINK1 variants detected in our Indian PD patient cohort. The Arg246 has been reported to be a mutational hotspot; since another mutation, Arg246stop, has been reported in other population including Japanese, Israeli PINK1 linked families and
Acknowledgement
The authors are thankful to the patients and normal healthy volunteers for participating in the study. The study has been supported by a grant from the Council of Scientific and Industrial Research (CSIR), Government of India (to JR), and a CSIR project CMM-0016 (to KR). AB is supported by a pre-doctoral fellowship from Indian Council of Medical Research (ICMR), India.
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Cited by (22)
Nonmotor Signs in Genetic Forms of Parkinson's Disease
2017, International Review of NeurobiologyParkinson's disease–related gene variants influence pre-mRNA splicing processes
2016, Neurobiology of AgingCitation Excerpt :Their overexpression in vitro can successfully correct not only 5′ss mutations where wt U1snRNAs naturally bind but also 3′ acceptor splice site mutations (Fernandez Alanis et al., 2012). The variants have been selected based on their association with PD risk (association studies, mutational screening), the lack of detailed functional analysis of their potential influence on splicing (except for PINK1 IVS7+1G>A for which we try rescue approach), and they have usually higher frequency than in control groups or database (Biswas et al., 2010; Cruts et al., 2012; De Mena et al., 2009; Gaweda-Walerych et al., 2010; Rakovic et al., 2011; Valente et al., 2004). For bioinformatic analysis of splicing impact, we used Human Splicing Finder (Desmet et al., 2009) and Clone Suite Manager v. 9.0.
Novel P-TEN-induced putative kinase 1 (PINK1) variant in Indian Parkinson's disease patient
2015, Neuroscience LettersCitation Excerpt :Two other non-synonymous SNPs (p.A340T and p.N521T) were also detected in either form of homozygous or heterozygous in C′ terminal lobe of Ser–Thr kinase domain and C′ terminal domain of PINK1, respectively. The p.A340T variant was reported earlier not to be associated with Indian PD population [15]. The SNPs observed in intronic and 3′ UTR region could not be predicted in silico to affect the protein structure, due to the limitation of the software.
Assessing the prevalence of PINK1 genetic variants in South African patients diagnosed with early- and late-onset Parkinson's disease
2010, Biochemical and Biophysical Research CommunicationsCitation Excerpt :However, preliminary analysis showed that the average AAO for patients with (44.1 ± 9.9 years; 30/154) and without (52.7 ± 12.5 years; 124/154) the IVS1-7 A > G variant was significantly different (p < 0.001; t-test). A few recent studies have reported either no PINK1 mutations in PD patients from Brazil [32], China [33] and Portugal [34] or only a few heterozygous variants of unknown pathogenic significance in patients from Australia [35] and India [36]. These findings are in contrast to the high frequencies observed in earlier studies.
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The review of this paper was entirely handled by an Associate Editor, En-King Tan.