LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8
ABSTRACT Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been found to cause typical, later-onset Parkinson disease (PD). Although G2019S is the most common mutation, other mutations have also been reported. It is critical to catalog the types of mutations found in LRRK2 that can cause PD, so as to provide insight regarding disease susceptibility and potential novel treatments.
We performed a comprehensive study of all 51 exons of the LRRK2 gene in one PD patient from each of 88 multiplex PD families who had the highest family-specific multipoint lod score at the LRRK2 locus from a cohort of 430 PD families without the G2019S mutation.
Five families (5.7%) harbored what seem to be novel, pathogenic mutations (L1795F, I1192V, E10K, E334K, Q1111H). Three of these apparent mutations were in known, functional domains of the LRRK2 protein, where other studies have also identified disease producing mutations. However, two of the novel variants were found in the N-terminal region of LRRK2, where no pathogenic substitutions have yet been reported. Similar to previous studies, all subjects with an LRRK2 mutation had classic symptoms of PD and typical, later age at onset.
We have identified five novel variants in LRRK2, with two of these in the N-terminal region of LRRK2, where no pathogenic substitutions have been previously reported. If confirmed to be causative, these mutations would broaden the potential mechanisms whereby mutations in LRRK2 result in Parkinson disease.
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ABSTRACT: Genetic variations of leucine-rich repeat kinase 2 (LRRK2) are the major cause of dominantly inherited Parkinson disease (PD). LRRK2 protein contains seven predicted domains: a tandem Ras-like GTPase (ROC) domain and C-terminal of Roc (COR) domain, a protein kinase domain and four repeat domains. PD-causative variations arise in all domains, suggesting that aberrant functioning of any domain can contribute to neurotoxic mechanisms of LRRK2. Determination of the three-dimensional structure of LRRK2 is one of the best avenues to decipher its neurotoxic mechanism. However, with the exception of the Roc domain, the three-dimensional structures of the functional domains of LRRK2 have yet to be determined. Based upon the known three-dimensional structures of repeat domains of other proteins, the tandem Roc-COR domains of the C. tepidum Rab family protein, and the kinase domain of the D. discoideum Roco4 protein, we predicted (i) the motifs essential for protein-protein interactions in all domains, (ii) the motifs critical for catalysis and substrate recognition in the tandem Roc-COR and kinase domains, and (iii) the effects of some PD-associated missense variations on the neurotoxic action of LRRK2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK2. This article is protected by copyright. All rights reserved.Human Mutation 04/2014; 35(4). DOI:10.1002/humu.22515 · 5.05 Impact Factor
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ABSTRACT: Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson's disease (PD). Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.10/2012; 5(2):33-41. DOI:10.14802/jmd.12009
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ABSTRACT: The LRRK2 gene (Leucine-Rich Repeat Kinase 2, PARK8) is mutated in a significant number of cases of autosomal dominant Parkinson's disease (PD) and in some sporadic cases of late-onset PD. LRRK2 is a large, complex protein that comprises several interaction domains: armadillo, ankyrin, leucine-rich repeats and WD40 domains; two catalytic domains: ROC-GTPase and serine/threonine kinase; and a COR domain (unknown function). Pathogenic mutations are scattered all over the domains of LRRK2, although the prevalence of mutations in some domains is higher (ROC-GTPase, COR and kinase). In this work, we model the structure of each domain to predict and explore the effects of described missense mutations and polymorphisms. The results allow us to postulate the possible effects of pathogenic mutations in the function of the protein, and hypothesize the importance of some polymorphisms that have not been linked directly to PD, but act as risk factors for the disease. In our analysis, we also study the effects of PD-related mutations in the kinase domain structure and in the phosphorylation of the activation loop to determine effects on kinase activity.Molecular Biology Reports 02/2014; DOI:10.1007/s11033-014-3111-z · 1.96 Impact Factor