We observed a mutation frequency of 8.5% in Parkin gene among Indian PD patients based on sequencing and gene dosage analysis of its exons. We identified nine point mutations of which seven are novel and hitherto unreported. These mutations accounted for 14.3% familial PD, 6.9% young onset and 5.9% late onset sporadic PD. Of the 20 PD patients with mutations only two had homozygous mutations and one was a compound heterozygote. Homozygous exonic deletions were absent but heterozygous exon rearrangements were observed in 9.2% of patients (19% familial PD and 4.5% young onset sporadic PD).
"Parkin gene encodes for Parkin protein (subunit of E3 ubiquitin ligase) involved in the proteosomal degradation. Chaudhary et al. analyzed the Parkin mutations in familial and sporadic Parkinson’s disease among Indians. They found that mutation frequency of 8.5% in the Parkin gene among Indian PD patients. "
[Show abstract][Hide abstract] ABSTRACT: Neuropsychiatric disorders represent the second largest cause of morbidity worldwide. These disorders have complex etiology and patho-physiology. The major lacunae in the biology of the psychiatric disorders include genomics, biomarkers and drug discovery, for the early detection of the disease, and have great application in the clinical management of disease. Indian psychiatrists and scientists played a significant role in filling the gaps. The present annotation provides in depth information related to research contributions on the molecular biology research in neuropsychiatric disorders in India. There is a great need for further research in this direction as to understand the genetic association of the neuropsychiatric disorders; molecular biology has a tremendous role to play. The alterations in gene expression are implicated in the pathogenesis of several neuropsychiatric disorders, including drug addiction and depression. The development of transgenic neuropsychiatric animal models is of great thrust areas. No studies from India in this direction. Biomarkers in neuropsychiatric disorders are of great help to the clinicians for the early diagnosis of the disorders. The studies related to gene-environment interactions, DNA instability, oxidative stress are less studied in neuropsychiatric disorders and making efforts in this direction will lead to pioneers in these areas of research in India. In conclusion, we provided an insight for future research direction in molecular understanding of neuropsychiatry disorders.
Indian Journal of Psychiatry 01/2010; 52(Suppl 1):S120-7. DOI:10.4103/0019-5545.69223
"Multiple sequence alignment and estimation of the tolerability of the observed parkin substitutions indicated that they were probably tolerable (Figure 2a). The reported frequency of parkin associated parkinsonism was similarly low in populations of India where the Gln34Arg substitution was previously observed [52,53]. "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Recent discovery of pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene in Parkinson's disease (PD) patients in different ethnic groups have raised a hope of diagnostic screening and genetic counseling. We investigated the six most commonly reported mutations in LRRK2 gene among Indian PD patients, using PCR-RFLP method. Mutations G2019S, R1441C, R1441G, and R1441H were screened in 1012 individuals (PD, 800; controls, 212) while mutations I2012T and I2020T were screened in 748 PD patients. We did not observe any of these six mutations in this study sample except in a single female young onset PD patient who showed a heterozygous G2019S mutation. The absence of mutations was reconfirmed by sequencing of probands from several autosomal dominant PD families. Our observations suggest that these mutations may be a rare cause of PD among Indians and therefore of little help for diagnostic screening and genetic counseling for Indian PD patients.
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