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DJ-1 mutations are a rare cause of recessively inherited early onset parkinsonism mediated by loss of protein function
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  1. P J Lockhart1,
  2. S Lincoln1,
  3. M Hulihan1,
  4. J Kachergus1,
  5. K Wilkes1,
  6. G Bisceglio1,
  7. D C Mash2,
  8. M J Farrer1
  1. 1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
  2. 2Department of Pathology, University of Miami, Miami, FL, USA
  1. Correspondence to:
 Dr P J Lockhart
 Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, USA, 32224; caseyandpaulhotmail.com

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Parkinson’s disease (PD; OMIM #168600) is a common neurodegenerative disorder characterised by bradykinesia, resting tremor, muscle rigidity, and postural instability. The pathological features include loss of dopaminergic neurones, in particular within the substantia nigra pars compacta, and eosinophilic, cytoplasmic inclusions termed Lewy bodies.1 Although rare, familial forms of parkinsonism provide a powerful tool to determine the molecular pathways perturbed in idiopathic PD.2,3

Three loci have been associated with autosomal recessive early onset parkinsonism (EO-PD): parkin (PARK2),4 the as yet unidentified PARK6,5 and DJ-1 (PARK7).6 Loss of Parkin function is the predominant genetic cause of EO-PD in Japanese, Northern European, North American, and North African populations. Homozygous and compound heterozygous parkin mutations account for approximately 49% of familial and 19% of sporadic EO-PD (with onset prior to 45 years).7–13 Although the gene has yet to be identified, linkage analysis of chromosome 1p36 interval suggests that PARK6 mutations may also account for numerous families with EO-PD across Europe.14 Most recently, mutations in DJ-1 (PARK7) were identified in consanguineous Dutch and Italian kindreds affected with EO-PD. In the Dutch kindred, a 14 kb genomic deletion removed the promoter region and the first five exons (Δ1−5). In the Italian kindred, a highly conserved amino acid (leucine) was altered to proline (497 bp T→C; L166P). This substitution was predicted to disrupt protein folding and was demonstrated to affect cellular localisation.6 Both mutations showed complete segregation with disease in homozygous individuals, while heterozygous carriers were unaffected, suggesting that loss of function of DJ-1 is pathogenic. To date, DJ-1 Δ1–5 and 497 bp T→C (L166P) mutations have only been reported in the original Dutch and Italian families and in ethnically matched control individuals.6 There have been no reports on the frequency of DJ-1 …

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