PINK1 mutation heterozygosity and the risk of Parkinson's disease

Department of Neuroscience, Norwegian University of Science and Technology (NTNU), N-7489 Trondheim, Norway.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 02/2007; 78(1):82-4. DOI: 10.1136/jnnp.2006.097840
Source: PubMed


Mutations in the PTEN-induced kinase 1 (PINK1) gene have been identified in recessively inherited and sporadic early-onset parkinsonism (EOP).
A total of 131 Norwegian patients diagnosed with Parkinson's disease were included. Of them, 89 participants had EOP (onset < or = 50 years); the remaining had familial late-onset disease (mean age at onset 64 years). PINK1 analysis included sequencing and gene dose assessment. Mutations were examined in 350 controls.
Heterozygous missense mutations in PINK1 were found in 3 of 131 patients; none of the patients carried homozygous or compound heterozygous mutations. One of these three patients had a father affected by Parkinson's disease, and he carried the mutation. Three new and seven known polymorphic variants were identified, although none seemed to be associated with disease risk.
PINK1 mutations are rare in Norwegian patients with EOP and familial Parkinson's disease. However, the data suggest that some heterozygous mutations might increase the risk of developing Parkinson's disease.

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Available from: Mathias Toft, Apr 15, 2014
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    • "balance regulation and consequently change the metabolic potency of cell. Most of the previous studies on PINK1 gene variations focussed on their association with Parkinson's disease (Toft et al. 2007; Kumazawa et al. 2008; Brooks et al. 2009). Due to few previous studies on the association of genetic variation in PINK1 gene with T2DM, only a few other groups provided indirect evidences on the role of PINK1 gene in the development of T2DM. "

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    • "The N521T substitution identified in this region is the most prevalent in our material and thus far one of the most common substitutions found in cases as well as healthy family members with parkinsonism. In previous studies the N521T substitution has been common and recognised merely as a polymorphism [45,58] and in studies of early-onset PD homozygous incidences have been confirmed in controls and cases equally [27,31]. "
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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.
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    • "For age-related diseases such as Parkinson disease, the mean age of late-onset Parkinson disease was estimated as 65 with SD<10 and as 45 with SD<10 for early-onset Parkinson disease in several studies [Oliveri et al., 2001; Toft et al., 2007; Clark et al., 2004]. Hence, it is not uncommon that the covariate means for two heterogeneous populations are 2 SD apart, as our simulation setup in Table II. "
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