Mutational screening of the parkin gene among South Indians with early onset Parkinson's disease

Sree Chitra Tirunal Institute for Medical Sciences and Technology, Tiruvananantapuram, Kerala, India
Journal of Neurology Neurosurgery & Psychiatry (Impact Factor: 6.81). 12/2005; 76(11):1588-90. DOI: 10.1136/jnnp.2004.046888
Source: PubMed


Parkin mutations are commonly encountered in multiethnic populations with familial early onset Parkinson's disease (PD) and less frequently in sporadic PD. A total of 102 patients (recruited from a hospital) with early onset PD from an ethnically homogeneous Indian population (age of onset < or =50 years) including both familial (n = 20) and sporadic (n = 82) cases were screened for parkin mutations. There were 105 normal controls. A homozygous missense mutation, Thr240Met, was found in exon 6 of one case and homozygous deletions of exons 8 and 9 were found in another index case. These constituted 2% of all early onset PD, 10% of all familial early onset PD, and 25% of all autosomal recessive early onset PD patients. No mutations were found in the patients with sporadic early onset PD, but seven exonic changes (three novel) were identified among 23 sporadic cases. These may represent heterozygous pathogenic changes. Use of more advanced techniques, including gene dosage estimation, and studies in Indian populations of different ethnic backgrounds may detect more mutations in future studies. This is the first report of parkin mutations from India and the first report from a non-white, non-oriental population of early onset PD.

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Available from: Asha Kishore, May 04, 2015
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    • "The Val380Leu mutation has, in previous studies, been found in both healthy and affected individuals. Abbas et al. [17] reported that the substitution was found in eleven European families and also 16% of the control subjects and it appear to be common across populations [52,54] and therefore not considered a main cause of disease development. It might, however, alter the Parkin protein and contribution to the pathogenesis of idiopathic PD, as noted in a study by Lucking et al. [55], which reported homozygous Val380Leu substitutions to be associated with sporadic PD. "
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    ABSTRACT: Parkinson's disease is a progressive neurodegenerative disorder, where most cases are sporadic with a late onset. In rare incidences familial forms of early-onset parkinsonism occur, and when recessively inherited, cases are often explained by mutations in either the parkin (PARK2) or PINK1 (PARK6) gene or on exceptional occasions the DJ-1 (PARK7) or ATP13A2 (PARK9) gene. Recessively inherited deletions/duplications and point mutations in the parkin gene are the most common cause of early-onset parkinsonism known so far, but in an increasing number of studies, genetic variations in the serine/threonine kinase domain of the PINK1 gene are found to explain early-onset parkinsonism. In this study all families were from a population with a high incidence of consanguinity. We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the parkin and PINK1 gene. Exons and flanking regions were sequenced, and segregation patterns of genetic variation were assessed in members of the respective families. An exon dosage analysis was performed for all exons in both genes. In the parkin gene, a three generation family was identified with an exon 4 deletion segregating with disease. Both affected were homozygous for the deletion that segregated on a haplotype that spanned the gene in a haplotype segregation analysis that was performed using additional markers. Exon dosage analysis confirmed the recessive pattern of inheritance with heterozygous deletions segregating in healthy family members. In the PINK1 gene we identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each. We also discuss common polymorphisms in the two genes found to be co-segregating within families. Our results further extend on the involvement of PINK1 mutations in recessive early-onset parkinsonism with clinical features similar to carriers of parkin mutations.
    BMC Neurology 01/2009; 8(1):47. DOI:10.1186/1471-2377-8-47 · 2.04 Impact Factor
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    • "The remaining 25% constitutes all other types (small deletion, insertion, gene duplication, etc.) of mutations. Despite extensive studies on the molecular bases of PD in different population groups, very little information is available regarding the molecular pathogenesis of the disease among Indians [11]. A single report has demonstrated the absence of known a-synuclein mutations (Ala30Pro and Ala53Thr), causal to PD, in Indian patients [12]. "
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    ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disorder, affects at least 1% of the population over the age of 50. However, very little information is available regarding the molecular basis of PD among Indians. Since the largest number of mutations have been detected in the Parkin gene among all known PD loci, we aim to use Parkin as the candidate gene to assess its role in PD-related pathogenesis in Indian patients. A total of 138 PD patients, with the mean age of onset being 47+/-14 (age range, 5-77 years), and 100 controls were recruited for the study from eastern India. Parkin mutations were detected by amplification of exons of the gene along with the flanking splice junctions by polymerase chain reaction, single-stranded conformation polymorphism and DNA sequencing. A total of 18 nucleotide variants including six novel changes were detected. These include five missense mutations (Gln34Arg, Arg42Cys, Arg42His, Tyr143Cys and Arg334Cys) detected in eight patients in heterozygous condition and a homozygous deletion encompassing exons 3 and 4 in two sibs affected with PD. Clinical features of the Parkin mutants were compared. Among eastern Indian PD patients, mutation in Parkin was identified in 7.24% cases.
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    ABSTRACT: Epidemiological research aims to provide information on the development, prevalence and progression of diseases, and their associated risk factors. Epidemiological research is thus the basis of increasing our understanding on the aetiology of diseases and as a consequence the starting point for identifying at risk groups in the population, development for novel prevention and treatment strategies, and health care planning. This review provides an overview of the epidemiology of Parkinson’s disease, the second most common neurodegenerative disorder, with special emphasis on population-based data on the clinical progression of motor and non-motor features of the disease.
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