Last, mutations in 2 of these genes turned out to be frequent enough to have relevance in clinical practice: parkin mutations are common in early-onset familial and sporadic PD; moreover, emerging data delineate mutations in the LRRK2 gene (encoding the dardarin protein) as a frequent cause of the familial late onset PD forms, and even of few late-onset sporadic cases.
To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease.
However, in vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate.
Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease.
These findings suggest a gain-of-function mechanism in the pathogenesis of LRRK2-linked PD and suggest that LRRK2 may be involved in a pathogenic pathway with other PD-related proteins such as parkin, which may help illuminate both familial and sporadic PD.
Therapeutic strategies targeted at modulating Lrrk2 kinase activity may be important to treat patients with genetically defined familial or typical sporadic Parkinson's disease.
The identification of mutations in six genes responsible for Mendelian forms of PD; alpha-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1, PTEN-induced putative kinase 1 (PINK1), and most recently leucine-rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease.
The "common" LRRK2G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease.
The G2019S mutation in the LRRK2 gene is reportedly a common cause of familial Parkinson's disease (PD) and may also have a significant role in nonfamilial PD.
Our data suggest that the LRRK2G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients.
The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.
Recently, a mutation in the LRRK2 gene, G2019S, was associated with 3-41% and 1-2% of familial and sporadic PD, respectively suggesting a pivotal role of LRRK2 in PD.
We show that LRRK2 immunoprecipitated from cells has a detectable GTPase activity that is disrupted by a familial mutation associated with PD located within the GTPase domain, R1441C.
The G2019Sleucine-rich repeat kinase 2 gene (LRRK2) mutation has been identified in a significant proportion of familial and sporadic cases of Parkinson's disease (PD).
The LRRK2G2019S mutation (c.6055G>A) is the most frequent substitution in Caucasians, accounting for approximately 5-6% of familial and 0.5-2.0% of apparently sporadic PD cases.
Insights from initial familial studies suggest that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive.
Based on these findings, Latourelle and colleagues show that the penetrance of the most common LRRK2 mutation is higher in patients with familial compared with sporadic Parkinson's disease and identified a substantial number of affected relatives of mutation carriers not presenting with a LRRK2 mutation themselves.