Research ReportParkin dosage mutations in patients with early-onset sporadic and familial Parkinson's disease in Chinese: An independent pathogenic role

Mutations in the parkin gene have been identified as one of the important genetic factors for the etiology of PD. However, pathogenicities of parkin mutations, especially of those heterozygotes, remain controversial, possibly due to confusions caused by the “mixed” effects of all types of mutations. Here we report a study on the independent effects of exonic deletions/duplications (or dosage mutations) on the risk for and clinical profiles of PD in a Chinese cohort consisting of 29 autosomal-recessive early-onset parkinsonism (AREP) families and 173 patients with sporadic early-onset Parkinson's disease (EOPD). Detected simultaneously by multiplex PCR/denaturing high-performance liquid chromatography and real-time quantitative PCR analysis, heterozygous or homozygous dosage mutations were identified in exons 2-7 of parkin. The overall frequency of these mutations for both types of EOPD patients (8.91%, 18/202) was significantly higher than that of the controls (0%, 0/54) (p = 0.03), and heterozygous mutations were more frequent in the AREP probands (17.2%, 5/29) than in the controls (0%) (p = 0.004) and the sporadic EOPD cases (3.5%, 6/173) (p = 0.01). AREP patients with dosage mutations had significantly younger age at onset (AAO) (p = 0.000) and were more likely to present as bradykinesia and complicated with dystonia or dyskinesia compared with those without mutations. Sporadic EOPD patients with dosage mutations do not have an earlier AAO but are more likely to present as tremor and bradykinesia. These data suggested that dosage mutations alone can increase the risk for both sporadic and familial EOPD and affect their clinical aspects, but might contribute to a greater degree to familial EOPD.

Research Highlights►Dosage mutations alone increase the risk for AREP and sporadic EOPD. ►Dosage mutations were more frequent in AREP than in sporadic EOPD. ►AREP, but not sporadic EOPD, with dosage mutations had younger age at onset.