Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease

Haugarvoll, Kristoffer; Rademakers, Rosa; Kachergus, Jennifer M.; Nuytemans, Karen; Ross, Owen A.; Gibson, J. M.; Tan, Eng King; Gaig, Carles; Tolosa, Eduardo; Goldwurm, Stefano; Guidi, Marco; Riboldazzi, Giulio; Brown, Laura A.; Walter, Uwe; Benecke, Reiner; Berg, Daniela; Gasser, Thomas; Theuns, Jessie; Pals, Philippe; Cras, Patrick; Deyn, Peter Paul De; Engelborghs, S.; Pickut, Barbara A.; Uitti, Ryan J.; Foroud, Tatiana; Nichols, William C.; Hagenah, Johann; Klein, Christine; Samii, Ali; Zabetian, Cyrus P.; Bonifati, Vincenzo; Broeckhoven, Christine Van; Farrer, Matthew J.; Wszołek, Zbigniew K.

doi:10.1212/01.wnl.0000304044.22253.03

Cited by 141 publications

(137 citation statements)

References 31 publications

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“…PD patients carrying the pathogenic LRRK2 R1441C or G2019S mutation exhibited clinical symptoms similar to idiopathic PD (31,46). Most of the patients showed late disease onset and symptoms of rigidity, bradykinesia, tremor, postural instability and levodopa response, which are similar to the sporadic PD cases (31).…”

Section: Pathogenic Lrrk2 Mutationsmentioning

confidence: 71%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

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Parkinson's disease (PD) is the second most common neurodegenerative disease, and 5-10% of the PD cases are genetically inherited as familial PD (FPD). LRRK2 (leucine-rich repeat kinase 2) was first reported in 2004 as a gene corresponding to PARK8, an autosomal gene whose dominant mutations cause familial PD. LRRK2 contains both active kinase and GTPase domains as well as protein-protein interaction motifs such as LRR (leucine-rich repeat) and WD40. Most pathogenic LRRK2 mutations are located in either the GTPase or kinase domain, implying important roles for the enzymatic activities in PD pathogenic mechanisms. In comparison to other PD causative genes such as parkin and PINK1, LRRK2 exhibits two important features. One is that LRRK2's mutations (especially the G2019S mutation) were observed in sporadic as well as familial PD patients. Another is that, among the various PDcausing genes, pathological characteristics observed in patients carrying LRRK2 mutations are the most similar to patients with sporadic PD. Because of these two observations, LRRK2 has been intensively investigated for its pathogenic mechanism (s) and as a target gene for PD therapeutics. In this review, the general biochemical and molecular features of LRRK2, the recent results of LRRK2 studies and LRRK2's therapeutic potential as a PD target gene will be discussed. [BMB reports 2010; 43(4): 233-244]

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Section: Pathogenic Lrrk2 Mutationsmentioning

confidence: 71%

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Seol

2010

BMB Reports

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“…Owing to a founder effect, the p.R1441G is very frequent in Basques (Simon-Sanchez et al 2006;Gorostidi et al 2009) and p.I2020T in Japanese patients . Whereas p.G2019S shows reduced penetrance, sometimes estimated to be as low as 24%, the p.R1441 mutation is highly penetrant (95% at the age of 75 yr) (Haugarvoll et al 2008).…”

Section: Lrrk2 (Park8)mentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

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Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

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“…The second most common LRRK2 mutation, R1441C, has been found in several different populations [79]. Interestingly, two other variations of the same codon (R1441G and R1441H) have been reported.…”

Section: Roc-cor Bidomain Mutationsmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease

Cited by 141 publications

References 31 publications

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease

Genetics of Parkinson's Disease

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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