Genetic reports abstractNegative resultsVPS35 and EIF4G1 mutations are rare in Parkinson's disease among Indians
Introduction
Parkinson's disease (PD) is a debilitating neurological disorder that results from progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta of the mid-brain, but the mechanism underlying neurodegeneration remains elusive. Attempts to unravel the genetic determinants of neurodegeneration are a major focus in PD research. To date, 18 PARK loci have been identified (Lesage and Brice, 2012), of which the mutation spectrum across different ethnic populations, in SNCA and LRRK2 for autosomal dominant Parkinson's disease (ADPD) (Sundal et al., 2012) and PARKIN, PINK1, and DJ1 for autosomal recessive juvenile parkinsonism (Bonifati, 2012), has been extensively documented. However, literature on the contribution of vacuolar protein sorting homolog 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), the 2 recently discovered ADPD genes, to diverse populations remains meager. The predominant p.Asp620Asn mutation in VPS35 has been found in 13 late-onset ADPD families of largely Caucasian descent (Lesage et al., 2012; Sheerin et al., 2012; Vilarino-Guell et al., 2011; Zimprich et al., 2011) and in 3 Japanese PD families (Ando et al., 2012) but absent in Chinese (Chen et al., 2013; Zhang et al., 2012). On the other hand, the common p.Arg1205His mutation in EIF4G1 has been observed only in familial and sporadic Caucasian PD cases (Chartier-Harlin et al., 2011).
We have previously shown that the mutation frequency in known genes such as SNCA and LRRK2 in familial PD (FPD) and sporadic PD (SPD) in the ethnically distinct Indian population is negligible (Nagar et al., 2001; Punia et al., 2006). In the case of LRRK2, the frequency is also vastly different from the global ethnic spectrum (Sundal et al., 2012). Thus, almost all of Indian ADPD cases are unexplained to date. Therefore, in this study, we determined the genetic contribution of VPS35 and EIF4G1, by screening for both reported and novel mutations in a moderately sized FPD and a representative SPD cohort from India.
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Methodology
A total of 69 familial and 251 sporadic PD subjects were included in this study. PD was diagnosed using the UK PD Brain Bank clinical diagnostic criteria (Hughes et al., 1992) by movement disorder specialists (MB and UBM). Subjects were recruited at 3 clinical centers, namely, All India Institute of Medical Sciences (AIIMS), New Delhi, National institute of Mental Health and Neurosciences (NIMHANS), Bangalore, and Parkinson's and Aging Research Foundation (PARF), Bangalore, after obtaining
Results
Resequencing of the entire exonic regions of VPS35 and EIF4G1 did not identify either reported or novel mutations in 15 probands with detailed family history of PD. In addition, both p.Asp620Asn in VPS35 and p.Arg1205His in EIF4G1 were also absent in an additional 54 FPD and 251 SPD cases and 100 healthy controls screened. Only, rs168745, a common synonymous single-nucleotide polymorphism, in exon 15 of VPS35 was observed in 6 of the 15 ADPD probands that were resequenced.
Discussion
Varying contribution of the 7 genes, namely, SNCA, LRRK2, VPS35, EIF4G1, PARKIN, PINK1, and DJ1 for Mendelian forms of PD has been witnessed across ethnic groups. Lack of known and novel mutations in the more recently reported genes, namely, VPS35 and EIF4G1 among familial and sporadic forms of PD observed in this study together with the previously reported absence of mutations in SNCA (Nagar et al., 2001) and LRRK2 (Punia et al., 2006) among Indian familial and sporadic PD cases reiterates the
Disclosure statement
There are no actual or potential conflicts of interest.
All subjects who participated in this study were recruited at 3 clinical centers, namely, AIIMS, New Delhi, NIMHANS, Bangalore, and PARF, Bangalore, after obtaining informed consent from study subjects and clearance from ethical committee of respective institutions.
Acknowledgements
The authors thank all the subjects who participated in this study. Financial assistance is from Department of Science and Technology, Govt of India, New Delhi (Grant #SP/SO/B-55/2000) and Department of Biotechnology, Govt of India, New Delhi (Grants # BT/PR2425/Med/13/089/2001 and #BT/PR14500/MED/12/478/2010) to BKT, MB, UBM, and RCJ; Council for Scientific and Industrial Research, New Delhi, for Junior Research Fellowship and Senior Research Fellowship to SS, Ms. Anjali Dabral for DNA
References (14)
Autosomal recessive parkinsonism
Parkinsonism Relat. Disord.
(2012)- et al.
Translation initiator EIF4G1 mutations in familial Parkinson disease
Am. J. Hum. Genet.
(2011) - et al.
VPS35 Asp620Asn and EIF4G1 Arg1205His mutations are rare in Parkinson disease from Southwest China
Neurobiol. Aging
(2013) - et al.
Role of Mendelian genes in “sporadic” Parkinson's disease
Parkinsonism Relat. Disord.
(2012) - et al.
Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease patients
Neurosci. Lett.
(2006) - et al.
Screening for VPS35 mutations in Parkinson's disease
Neurobiol. Aging
(2012) - et al.
Autosomal dominant Parkinson's disease
Parkinsonism Relat. Disord.
(2012)