Clinical heterogeneity of the LRRK2 G2019S mutation

University of Miami, كورال غيبلز، فلوريدا, Florida, United States
JAMA Neurology (Impact Factor: 7.01). 10/2006; 63(9):1242-6. DOI: 10.1001/archneur.63.9.1242
Source: PubMed

ABSTRACT Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene (LRRK2) that cause parkinsonism. The "common" LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease.
To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers.
We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T.
Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations.
Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants.
The underlying disease mechanisms of LRRK2 G2019S-associated parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.

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    ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinson's disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case-control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities.
    Parkinsonism & Related Disorders 05/2012; 18(6):722-30. DOI:10.1016/j.parkreldis.2012.04.013 · 4.13 Impact Factor
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    ABSTRACT: Background: Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2; PARK8) encoding dardarin, implicated in patients with autosomal dominant and sporadic Parkinson’s disease (PD) among different ethnic groups (Ashkenazi Jews, North African Arabs, Basques) might be of some help in diagnostic screening and genetic counseling. Aim of the Study: We investigated the seven common mutations spanning exons 31, 35, and 41 reported in the LRRK2 gene among Eastern Indian patients with PD. Methods: Mutations R1441G, R1441C, R1441H, G2019S, Y1699C, I2020T, and I2012T were screened in 320 individuals (PD, 150 and controls, 170) by direct sequencing. Results: We did not observe any of these abovementioned mutations in our studied individuals. Conclusion: We conclude that these mutations are rare causes of PD in the Eastern Indian population and, therefore, of little help for genetic counseling and diagnostic purposes.
    Genetic Testing and Molecular Biomarkers 10/2010; 14. DOI:10.1089/gtmb.2010.0054 · 1.15 Impact Factor


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Jun 5, 2014