Parkin mutations are frequent in patients with isolated early‐onset parkinsonism

Abstract

Parkin gene mutations are reported to be a major cause of early-onset parkinsonism (age at onset < or = 45 years) in families with autosomal recessive inheritance and in isolated juvenile-onset parkinsonism (age at onset <20 years). However, the precise frequency of parkin mutations in isolated cases is not known. In order to evaluate the frequency of parkin mutations in patients with isolated early-onset parkinsonism according to their age at onset, we studied 146 patients of various geographical origin with an age at onset < or = 45 years. All were screened for mutations in the parkin gene using semi-quantitative polymerase chain reaction combined with sequencing of the entire coding region. We identified parkin mutations in 20 patients including three new exon rearrangements and two new missense mutations. These results, taken in conjunction with those of our previous study (Lücking et al., 2000) show that parkin mutations account for at least 15% (38 out of 246) of our early-onset cases without family history, but that the proportion decreases significantly with increasing age at onset. There were no clinical group differences between parkin cases and other patients with early-onset parkinsonism. However, a single case presenting with cerebellar ataxia several years before typical parkinsonism extends the spectrum of parkin related-disease.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Mutations in the parkin gene at PARK2 are the most frequent known cause of earlyͲonset (<40Ͳ 50 years) PD (10Ͳ20% worldwide; 50% of recessive familial forms) [216,217]. Pathological changes include significant loss of dopaminergic neurons in the SN and milder changes in the locus coeruleus.…”

Identification of a Novel Zn2+-binding Domain in the Autosomal Recessive Juvenile Parkinson-related E3 Ligase Parkin

“…The hereditary nature of ARJP implicates a number of mutations in the genes encoding the proteins parkin, PINK1, LRRK2, and DJ-1 as the cause of dopaminergic neurodegeneration (1-4). A variety of deletion, truncation, and point mutations distributed throughout the park2 gene, which encodes the protein parkin, have been reported in ARJP patients (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

“…The hereditary nature of ARJP implicates a number of mutations in the genes encoding the proteins parkin, PINK1, LRRK2, and DJ-1 as the cause of dopaminergic neurodegeneration (1-4). A variety of deletion, truncation, and point mutations distributed throughout the park2 gene, which encodes the protein parkin, have been reported in ARJP patients (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).Parkin functions as a ubiquitin ligase (E3) and belongs to a family of RBR (RING-between-RING) ubiquitin ligase enzymes involved in proteosome-mediated protein degradation (19 -21). The currently accepted domain architecture of parkin, deduced from multiple sequence alignment, shows that the C terminus of the protein is characterized by two ϳ50-residue RING (really interesting new gene) domains separated by a 51-residue IBR (In-Between-RING) domain (22,23).…”

Estrogen Metabolites in the Etiology of Hormone Related Cancers: Possible Role of Anti-Oxidants in Prevention

“…Investigation of biomarker excretion was performed in 20 PD patients on dopamine agonists compared to 40 control pts without PD [44]. Of estrogen metabolites analyzed, significantly higher levels (p=.004) of thiol (glutathione mediated) and methoxy (COMT derived) conjugates were noted in controls.…”