In this study, we performed a comprehensive mutation analysis of the PINK1
gene in a series of 131 patients. Mutations in the PINK1
gene seem to be rare in Norwegian patients diagnosed with Parkinson's disease. We identified three heterozygous mutation carriers; none of the patients had homozygous or compound heterozygous PINK1
mutations. Deletions and multiplications of the PINK1
gene are uncommon, as only one exonic deletion has been reported.8
Also, our quantitative analysis failed to detect any such mutations.
Two patients were heterozygous carriers of a PINK1
Gly411Ser substitution. One of them (P392) has a family history of Parkinson's disease, and his affected father carries the mutation, indicating a possible pathogenic role of this variant. Recently, a male patient with EOP starting at the age of 13 years was also found to be a heterozygous carrier of this mutation.15
A second previously unknown mutation, Pro489Leu, was found in a patient with late‐onset Parkinson's disease with a familial history of parkinsonism, but DNA from family members was not available for segregation analysis.
The clinical presentation of our three patients with PINK1
‐associated EOP was indistinguishable from idiopathic Parkinson's disease and similar to that found in most other families and sporadic cases with PINK1
All patients had a slowly progressive parkinsonian syndrome; none of them showed signs of early dementia, had psychiatric symptoms or had dystonia at disease onset. Only one of our patients has received dopaminergic treatment and showed an excellent effect of levodopa treatment. She developed severe dyskinesias, which have been successfully treated with implantation of bilateral stimulators in the subthalamic nuclei.
The pathogenic significance of a single heterozygous PINK1 mutation is unclear. In most autosomal recessive disorders heterozygous carriers are clinically unaffected. However, there is evidence that heterozygous PINK1 mutation carriers might be at increased risk of developing parkinsonism. The two mutations found in this study were absent in a large number of Norwegian control chromosomes, making it less likely that they are rare polymorphisms. Both mutations are located in the PINK1 kinase domain and replace evolutionary conserved amino acids, and may thus affect the kinase activity.
A positron emission tomography study of unaffected heterozygous PINK1
mutation carriers indicated a reduction in F‐dopa uptake in comparison with controls.16
dysfunction might reduce striatal dopamine storage capacity and increase susceptibility to parkinsonism. Similarly, positron emission studies of mutation carriers in the parkin
gene have shown a decreased F‐dopa uptake compared with controls.17
Several studies have reported high frequencies of single‐allele mutations in the parkin
gene of patients with EOP, suggesting that single parkin
mutations might be a risk factor for Parkinson's disease.18
has recently been shown to genetically interact with parkin
in model systems, indicating that the two proteins act in a common pathway.19
mutation screening of sporadic EOP cohorts from other European populations have identified findings similar to those in our Norwegian sample, with heterozygous mutations in patients that are absent in controls.10,11,20
In addition, six carriers of PINK1
mutations in a large German family with Parkinson's disease presented with slight or mild symptoms of disease.21
Although it remains unclear to what degree a single PINK1
mutation is a risk factor for parkinsonism, our findings support the possibility.