PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum

Hum Mutat. 2008 Apr;29(4):565. doi: 10.1002/humu.20719.


Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Case-Control Studies
  • Female
  • Gene Frequency
  • Genes, Recessive
  • Genetic Variation*
  • Heterozygote
  • Humans
  • Italy
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics*
  • Phenotype
  • Protein Kinases / genetics*
  • Retrospective Studies
  • Sequence Homology, Amino Acid


  • Protein Kinases
  • PTEN-induced putative kinase