PINK1 mutations are associated with sporadic early‐onset parkinsonism

Abstract

We have recently reported homozygous mutations in the PINK1 gene in three consanguineous families with early-onset parkinsonism (EOP) linked to the PARK6 locus. To further evaluate the pathogenic role of PINK1 in EOP and to draw genotype-phenotype correlates, we performed PINK1 mutation analysis in a cohort of Italian EOP patients, mostly sporadic, with onset younger than 50 years of age. Seven of 100 patients carried missense mutations in PINK1. Two patients had two PINK1 mutations, whereas in five patients only one mutation was identified. Age at onset was in the fourth-fifth decade (range, 37-47 years). The clinical picture was characterized by a typical parkinsonian phenotype with asymmetric onset and rare occurrence of atypical features. Slow progression and excellent response to levodopa were observed in all subject. Two of 200 healthy control individuals also carried one heterozygous missense mutation. The identification of a higher number of patients (5%) than controls (1%) carrying a single heterozygous mutation, along with previous positron emission tomography studies demonstrating a preclinical nigrostriatal dysfunction in PARK6 carriers, supports the hypothesis that haploinsufficiency of PINK1, as well as of other EOP genes, may represent a susceptibility factor toward parkinsonism. However, the pathogenetic significance of heterozygous PINK1 mutations still remains to be clarified.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Thus, similar to Parkin, it seems as haploinsufficiency of the PINK1 gene may cause susceptibility to sporadic PD. All mutations were point mutations or substitutions of a few nucleotides [231].…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…There is evidence that WT PINK1 in contrast to mutant PINK1 may protect neurons from stressͲinduced mitochondrial dysfunction and apoptosis [245]. Furthermore, loss of PINK1 function in human cell lines originated morphological changes of mitochondria and impaired energy metabolism, showed by a decreased mitochondrial membrane potential [243].…”

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

“…Heterozygous mutations of PINK1 were also detected in sporadic PD cases (11,12). The PINK1 gene encodes a putative kinase that acts on yet unidentified substrates and contains an N-terminal mitochondrial targeting motif (4).…”