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Parkin and PINK1 mutations in early-onset Parkinson’s disease: comprehensive screening in publicly available case-control cohorts
  1. Janet Brooks (brooksja{at}
  1. National Institute on Aging, United States
    1. Jinhui Ding (jd486s{at}
    1. National Institute on Aging, United States
      1. Javier Simon-Sanchez (simonsanchezj{at}
      1. National Institute on Aging, United States
        1. Coro Paisan-Ruiz (c.paisan-ruiz{at}
        1. Institute of Neurology, United Kingdom
          1. Andrew Singleton (singleta{at}
          1. National Institute on Aging, United States
            1. Sonja Scholz (scholzs{at}
            1. National Institute on Aging, United States


              Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease, or lower the age of disease onset, has been suggested, but currently there is insufficient data to conclusively verify this hypothesis.

              Objective: To study the frequency and spectrum of parkin and PINK1 gene mutations, and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson’s disease.

              Methods: We sequenced all exons and exon-intron boundaries of PINK1 and parkin in 250 early-onset Parkinson’s disease patients and 276 normal controls. We furthermore performed gene dosage measurements using high-density SNP arrays.

              Results: We discovered a total of 41 variants, of which eight have not been previously described (parkin: p.A38VfsX6, p.C166Y, p.Q171X, p.D243N, p.M458L; PINK1: p.P52L, p.T420T, p.A427G). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was overrepresented in patients as compared to healthy controls (4.00% vs. 1.81%) but the difference was not statistically significant (p-value 0.13). There was no significant difference in the mean age at disease onset in heterozygous patients compared to patients without a mutation in parkin or PINK1 (mean difference = 2 years, 95% CI= -3.7 to 7.0, p-value = 0.54).

              Conclusions: Our data supports a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared to normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls.

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