Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain

Mata, Ignacio; Hutter, Carolyn M.; González-Fernández, M.C.; Pancorbo, Marian M. de; Lezcano, Elena; Huerta, Cecilia; Blázquez, Marta; Ribacoba, René; Guisasola, Luis M.; Salvador, Carlos; Gómez‐Esteban, Juan Carlos; Zarranz, J.J.; Infante, Jon; Jankovic, Joseph; Deng, Hao; Edwards, Karen L.; Álvarez, Victoria; Zabetian, Cyrus P.

doi:10.1007/s10048-009-0187-z

Cited by 39 publications

(26 citation statements)

References 42 publications

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“…One example is R1441G associated with PD in the Basque region (Gorostidi et al 2009, Mata et al 2009a. Similarly, no carriers of R1441G, R1441C, or R1441H mutations were found among our cases.…”

Section: Discussionsupporting

confidence: 59%

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Bognár¹,

Baldovič²,

Benetin³

et al. 2013

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Abstract. Parkinson disease (PD) is a chronic neurodegenerative movement disorder characterized by selective loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies. Clinical manifestations include motor impairments involving tremor, bradykinesia, postural instability and rigidity.Using dHPLC method we screened exons 31, 35, 41, 48 of the Leucine-rich repeat kinase 2 (LRRK2) gene and exons 2, 6 and 7 of Parkinson protein 2 (parkin, PARK2) genes in a cohort of 216 consecutive, unrelated Slovak patients with familial or sporadic PD, including early and late onset. By this means we aimed to detect the most common pathogenic mutations within LRRK2 (Arg1441Cys, Arg1441Gly, Arg1628Pro, Tyr1699Cys, Gly2019Ser, Ile2020Thr, Gly2385Arg) and parkin genes responsible for late and early onset forms of disease, respectively. However, none of these mutations was identified in our cohort. Heterozygous point mutation p.Arg275Trp in exon 7 of parkin gene was identified in one patient with age at onset 61 years. Furthermore, we observed the presence of one exonic (LRRK2 ex 48: 7155A>G) and eight intronic polymorphisms (in LRRK2: IVS35+23T>A, IVS47-91insGCCAT, IVS47-91insGCAT, IVS47-41A>G, IVS47-9delT, IVS47-20C>T, IVS47-90A>G, in parkin: IVS2+25T>C), three of which were novel.

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Section: Discussionsupporting

confidence: 59%

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Bognár¹,

Baldovič²,

Benetin³

et al. 2013

gpb

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“…As a matter of fact, we had been able to link three of the four initially reported families as far as three centuries ago, suggesting that the same could occur with all other families analyzed, based on a common ancestral origin, as has been previously reported. 17,18 It was therefore considered appropriate to group the individuals into sibships. However, in familybased studies there is a selection bias due to more ready ascertainment of families with multiple affected relatives.…”

Section: Discussionmentioning

confidence: 99%

“…16 Nowadays, this mutation continues being mainly present in the Basque Country, where a common founder haplotype has been described, 17 and the age of the most recent common ancestor was estimated in approximately the seventh century. 18 This study reports the estimated age-dependent penetrance of the LRRK2 R1441G mutation derived from the largest published sample of PD cohort originated from the same population. This study of LRRK2 R1441G penetrance provides information for accurate genetic counseling and together with the information previously reported in LRRK2 G2019S mutation studies may contribute to a better understanding of the pathogenetic mechanisms of the disease.…”

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confidence: 99%

Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain)

et al. 2010

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The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance.

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“…Mutations in LRRK2 account for 1-40% of all PD depending upon the ethnic background (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Reevaluation of Phosphorylation Sites in the Parkinson Disease-associated Leucine-rich Repeat Kinase 2

Moore

Xiong

et al. 2010

Journal of Biological Chemistry

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as an important cause of late-onset, autosomal dominant familial Parkinson disease and contribute to sporadic Parkinson disease. LRRK2 is a large complex protein with multiple functional domains, including a Roc-GTPase, protein kinase, and multiple protein-protein interaction domains. Previous studies have suggested an important role for kinase activity in LRRK2-induced neuronal toxicity and inclusion body formation. Disease-associated mutations in LRRK2 also tend to increase kinase activity. Thus, enhanced kinase activity may therefore underlie LRRK2-linked disease. Similar to the closely related mixed-lineage kinases, LRRK2 can undergo autophosphorylation in vitro. Three putative autophosphorylation sites (Thr-2031, Ser-2032, and Thr-2035) have been identified within the activation segment of the LRRK2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of LRRK2. Sensitive phopho-specific antibodies to each of these three sites have been developed and validated by ELISA, dot-blot, and Western blot analysis. Using these antibodies, we have found that all three putative sites are phosphorylated in LRRK2, and Ser-2032 and Thr-2035 are the two important sites that regulate LRRK2 kinase activity. Leucine-rich repeat kinase 2 (LRRK2)3 is a large multidomain-containing protein that plays a prominent role in Parkinson disease (PD) (1, 2). Mutations in LRRK2 account for 1-40% of all PD depending upon the ethnic background (3-8).Patients with penetrated mutations have clinical and neuropathologic features that are indistinguishable from idiopathic PD (9, 10). LRRK2 contains repeat sequences beginning at the N terminus as well as leucine-rich repeats. In addition, it contains a kinase effector domain and a guanosine triphosphatase (GTPase) domain that is spanned by a C-terminal Ras domain.There is a WD40 domain at its C terminus that is thought to mediate protein-protein interactions (7). Localization studies indicate that LRKK2 is localized primarily to cytosolic membranous structures (11,12). The exact physiologic function of LRRK2 is not known, but recent studies suggest that it may regulate neuronal polarity (13,14).LRRK2 is regulated by the ubiquitin proteasome system where its levels are controlled by the C terminus of HSP70-interacting proteins (CHIP). CHIP regulates the levels of LRRK2 through an HSP90 chaperone-containing complex. LRRK2 toxicity can be reduced by increasing CHIP E3 ligase activity and reducing HSP90 chaperone activity (15). Familial mutations in LRRK2 are thought to increase LRRK2 kinase activity, although there may be some PD-associated mutations that have minimal detectable effects on kinase activity (16 -18). LRRK2 overexpression leads to cytotoxicity that is kinase-and GTP binding-dependent (16,19,20). Because LRRK2 toxicity requires kinase activity, there is tremendous interest in understanding the molecular underpin...

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Lrrk2 R1441G-related Parkinson’s disease: evidence of a common founding event in the seventh century in Northern Spain

Cited by 39 publications

References 42 publications

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain)

Reevaluation of Phosphorylation Sites in the Parkinson Disease-associated Leucine-rich Repeat Kinase 2

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