LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease

Infante, Jon; Rodríguez, Eloy Rodríguez; Combarros, Onofre; Mateo, Ignacio; Fontalba, Ana; Pascual, Julio; Oterino, Agustı́n; Polo, J. M.; Leno, Carlos; Berciano, José

doi:10.1016/j.neulet.2005.10.083

Cited by 70 publications

(55 citation statements)

References 12 publications

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“…We will discuss these different mutations below based on where they are in the protein as this leads most easily into a discussion about variable effects on function. The most common LRRK2 mutation is G2019S, which was first identified in PD patients of European ancestry [60][61][62][63]. The highest incidence of this variant is in people of Ashkenazi Jewish descent (almost 20 %) [64] and in North African patients (about 40 %) [65].…”

Section: Diversity Of Lrrk2 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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Section: Diversity Of Lrrk2 Mutationsmentioning

confidence: 99%

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

Rudenko

Cookson

2014

Neurotherapeutics

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“…Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients (Brás et al 2005;Lesage et al 2005Lesage et al , 2006Lesage et al , 2008Clark et al 2006;Deng et al 2006;Gaig et al 2006;Goldwurm et al 2006;Infante et al 2006;Ozelius et al 2006;Marongiu et al 2006;Mata et al 2006Mata et al , 2009bCivitelli et al 2007;Cossu et al 2007;Ferreira et al 2007;González-Fernández et al 2007;Ishihara et al 2007;Orr-Urtreger et al 2007;Perez-Pastene et al 2007;Squillaro et al 2007;Hulihan et al 2008;Munhoz et al 2008;Pimentel et al 2008;Correia Guedes et al 2009;De Rosa et al 2009;Floris et al 2009;Gorostidi et al 2009). …”

Section: Discussionmentioning

confidence: 99%

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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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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“…The frequency of LRRK2 G2019S in patients with idiopathic Parkinson's disease is highest in North Africa (Lesage et al, 2006;Ishihara et al, 2007) and in Western Europe (Bras et al, 2005;Infante et al, 2006), 4-6% in Portugal and Spain. The first North African Arab-Berber study (Warren et al, 2008) estimated that the common founder lived 2,600 years ago, and an older age of 3,200 years ago is found in the present study in Berbers.…”

Section: Discussionmentioning

confidence: 99%

New contribution on the <i>LRRK2</i> G2019S mutation associated to Parkinson’s disease: age estimation of a common founder event of old age in Moroccan Berbers

Lucotte¹,

Dávid²,

Change³

2012

Int.J.Mod.Anthrop

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-Background:The LRRK2 G2019S mutation is an important genetic determinant of Parkinson's disease (PD) across the world that occurs at an elevated frequency in North Africa. Aim: To estimate the date of the G2019S mutation in Berbers. Material and Methods: We determined the LRRK2 haplotypes in twenty-two G2019S carriers, mostly North Africans, and in one hundred twenty-four Arab, Moroccan Berber and Sephardi Jew controls, using seven microsatellite and two SNP genetic markers. Results: A single haplotype was detected, with some variations, in all mutation carriers. Using a maximum-likelihood method, we estimate that Moroccan Berbers with G2019S share a common ancestor who lived ~128 (95% CI 107-180) generations ago. Conclusion: Our conclusion is that the G2019S mutation of the LRRK2 gene originates 3,840 (95% CI 3,210-5,400) years ago in parkinsonian Moroccan Berbers patients.

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LRRK2 G2019S is a common mutation in Spanish patients with late-onset Parkinson's disease

Cited by 70 publications

References 12 publications

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

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

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

New contribution on the <i>LRRK2</i> G2019S mutation associated to Parkinson’s disease: age estimation of a common founder event of old age in Moroccan Berbers

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