DJ-1 mutations are a rare cause of recessively inherited early onset parkinsonism mediated by loss of protein function.

P arkinson’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. Although rare, familial forms of parkinsonism provide a powerful tool to determine the molecular pathways perturbed in idiopathic PD. 3 Three loci have been associated with autosomal recessive early onset parkinsonism (EO-PD): parkin (PARK2), the as yet unidentified PARK6, and DJ-1 (PARK7). 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). 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. 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 (D125). In the Italian kindred, a highly conserved amino acid (leucine) was altered to proline (497 bp TRC; L166P). This substitution was predicted to disrupt protein folding and was demonstrated to affect cellular localisation. 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 D1–5 and 497 bp TRC (L166P) mutations have only been reported in the original Dutch and Italian families and in ethnically matched control individuals. There have been no reports on the frequency of DJ-1 variants in EO-PD generally, or in samples from other populations. DJ-1 appears to have several functions within the cell. Originally recognised as a c-myc interacting protein, DJ-1 has been identified as an infertility related protein, associated with RNA stabilisation and shown to convert to a more acidic form under conditions of oxidative stress. Currently, the mechanism by which loss of DJ-1 causes parkinsonism is unclear. With this background, we performed a comprehensive mutation analysis of DJ-1 in a cohort of 49 EO-PD probands, white subjects derived from North America and representing several European ethnicities. One sequence alteration was identified in one patient, a heterozygous 293 bp GRA transition, resulting in an R98Q change to the protein sequence. Subsequently, the functional properties of DJ-1 wild type, Q98, and P166 proteins were assessed. MATERIALS AND METHODS Patients All subjects were evaluated by a neurologist specialising in movement disorders and met the criteria for PD. Age of onset of PD symptoms was prior to 50 years (mean (SD) 38.6 (8.1) years; male:female = 32:9, unknown gender = 8; n = 49), and two (possible PD, n = 33) or three (probable PD, n = 15) of the four cardinal signs of PD were noted. Patients displayed no atypical features or evidence of secondary parkinsonism caused by other neurological disease or drugs/toxins, except for one, where the patient was diagnosed with resting tremor/parkinsonism but was included in this study because of the very early age of onset (18 years). All patients were white, of diverse North American and/or Northern European ethnicity. Twenty four probands were defined as sporadic PD, while 22 probands had a family history of PD, here defined as having one or more first degree relatives with PD, and three probands