Parkin mutations in familial and sporadic Parkinson's disease among Indians
Introduction
The past few years have seen tremendous progress in molecular genetics of Parkinson's disease (PD) leading to identification of six genes (namely, alpha synuclein, Parkin, UCH L1, PINK 1, DJ 1 and LRRK 2) and four chromosomal loci (namely, PARK3, 9, 10 and 11) in different types of PD [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. However, these account for mutations in only a small proportion of Mendelian forms of this disease. PARKIN, DJ-1 and PINK 1 mutations have been observed in autosomal recessive juvenile Parkinsonism [2], [6], [7]. Parkin and DJ-1 mutations are important causes for familial PD [11], [12] with Parkin being the commonest for autosomal recessive juvenile Parkinsonism (ARJP) [2]. Diverse frequency and a wide spectrum of mutations including point mutations, insertions and deletions within the Parkin gene have been reported in different ethnic populations [13], [14], [15], [16], [17]. The frequency of mutations has varied from 66% among Japanese [13] to 50% among Europeans [14], 9% among Germans and 4% among Americans [15], [16], [17]. In young onset cases with a family history but not conforming to the autosomal recessive mode of inheritance, a mutation frequency of 10–25% has been reported [18].
Mutations in Parkin gene are not restricted to familial cases but have also been observed in a few sporadic young onset and late onset cases. Most of these studies are difficult to compare due to differences in methods used to screen mutations by different groups and also due to the heterogeneity of the samples analysed. However, since Parkin gene seems to contribute substantially to idiopathic PD cases (familial/sporadic, early/late onset) across diverse ethnic groups, we evaluated Parkin mutation(s) among familial and sporadic young onset (YO; age of onset ≤40 years) and late onset (LO; age of onset ≥41 years) PD patients from India, using DNA sequencing and gene dosage estimation methods. Further, since Indians have different ethnic origins, we stratified our patients based on their North Indian or South Indian origin for purpose of comparison of mutation frequency between these two subsets.
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Subjects and methods
Patients were diagnosed as PD by movement disorder specialists located in two major hospitals, All India Institute of Medical Sciences, New Delhi (North India) and National Institute of Mental Health and Neurosciences, Bangalore (South India) during the period 1998–2003 according to the UK Parkinson's Disease Society Brain Bank Research criteria, London [19]. Clinical diagnosis was established with the presence of atleast two of the cardinal symptoms (resting tremors, bradykinesia, postural
Demographic data
Table 1 shows the demographic data of the 259 PD patients who were analyzed for Parkin mutations. Of these, 206 (141 YOPD, 48 LOPD and 17 familial PD) were from North India and 53 (32 YOPD, 3 LOPD and 18 familial PD) from South India. One family from South India was consanguineous.
Point mutations in Parkin
Twenty patients (7.7%) had point mutations in the Parkin gene, of which seven were missense and two were silent. Amongst these, seven were novel to the Indian population and hitherto unreported. Of the nine mutations
Discussion
At present, Parkin mutations are commonly described in early onset familial PD and occasionally in sporadic PD. Homozygous mutations have been reported in autosomal recessive early onset cases and heterozygous mutations are observed in late onset cases [22]. A wide spectrum of mutations with varying frequencies has been reported across different ethnic groups. Mutations in the Parkin gene have either been screened using techniques such as PCR followed by complete sequencing of the exonic
Acknowledgements
Financial assistance through grants DST SP/SO/B-55/2000 (to RCJ, BKT, MB, UM); ICMR SWG/Neurology/14/2001-NCD-1 (to MB, BKT, RCJ); ICMR 63/98/2001-BMS (to UM) and CSIR-SRF (to SC); and infrastructure support from DST-FIST are gratefully acknowledged.
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