Parkin mutations in familial and sporadic Parkinson's disease among Indians

https://doi.org/10.1016/j.parkreldis.2005.12.004Get rights and content

Abstract

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).

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.

Section snippets

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.

References (35)

  • V. Bonifati et al.

    Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism

    Science

    (2003)
  • E.M. Valente et al.

    Hereditary early-onset Parkinson's disease caused by mutations in PINK1

    Science

    (2004)
  • M. Funayama et al.

    A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1

    Ann Neurol

    (2002)
  • D.J. Hampshire et al.

    Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36

    J Med Genet

    (2001)
  • A.A. Hicks et al.

    A susceptibility gene for late-onset idiopathic Parkinson's disease

    Ann Neurol

    (2002)
  • D.G. Healy et al.

    DJ-1 mutations in Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (2004)
  • K. Hedrich et al.

    DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease

    Neurology

    (2004)
  • Cited by (40)

    • Event-related potential changes due to early-onset Parkinson's disease in parkin (PARK2) gene mutation carriers and non-carriers

      2020, Clinical Neurophysiology
      Citation Excerpt :

      Mutations in the parkin gene (also known as PARK2) on chromosome 6q are by far the most representative autosomal recessive forms of early-onset parkinsonism with earlier and more symmetrical onset, slower progression, and better response to levodopa compared with idiopathic EOPD (Lücking et al., 2000; Bonifati et al., 2001; Lohmann et al., 2003; Poorkaj et al., 2004; Tan and Skipper, 2007). A number of mutations in PARK2 have been reported in patients with familial or sporadic parkinsonism from several ethnicities (Alvarez et al., 2001; Gouider-Khouja et al., 2003; Chaudhary et al., 2006; Deng et al., 2008; Taylor et al., 2009; Bardien et al., 2009), also PARK2 mutations were reported to be the most frequent forms of autosomal recessive PD in Turkey (Lohmann et al., 2012). Biochemical and genetic studies reveal that the PARK2 mutation leads to the mitochondrial damage involved in PD (Pickrell and Youle 2015).

    • Nonmotor Signs in Genetic Forms of Parkinson's Disease

      2017, International Review of Neurobiology
    • Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease

      2016, Progress in Neurobiology
      Citation Excerpt :

      The onset of familial PD is attributed mainly to hereditary factors, while the etiology of those most sporadic cases is now known, or may be composed of environmental and other acquired factors (Calne, 1994; Maetzler et al., 2007; Takahashi et al., 2009). The differentiated approach to familial and sporadic forms of PD may display in some neuropathological features, rather than the pathogenesis and clinical features (Chaudhary et al., 2006; Schiesling et al., 2008; Vibha et al., 2010). To date, although the pathogenesis of PD remains elusive, a number of pathogenic proteins have been confirmed to be responsible for driving the progression of this disease, which may not only play a role in familial PD, but sporadic PD as well (Bonifati, 2007; Dawson and Dawson, 2010).

    • PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus

      2016, Annals of Hepatology
      Citation Excerpt :

      It was originally discovered as a cause of autosomal recessive juvenile parkinsonism25 and since then it has subsequently been linked to leprosy,26–28 autism,29 type 2 diabetes mellitus,30 Alzheimer disease31 and some types of cancer.32,33 Further, heterozygous mutations in PARK2 gene also exist and are considered to be more controversial with regard to disease association.34 A study found that variants in the shared PARK2 and PACRG regulatory region act as a risk factor for infection by Mycobacterium leprae, as a strong association was demonstrated between the PARK2_e01(-2599) polymorphism and leprosy.28

    View all citing articles on Scopus
    View full text