G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Lesage, Suzanne; Ibáñez, Pablo; Lohmann, Ebba; Pollak, Pierre; Tison, François; Tazir, M.; Leutenegger, Anne-Louise; Guimarães, João Tiago; Bonnet, Anne‐Marie; Agid, Yves; Dürr, Alexandra; Brice, Alexis

doi:10.1002/ana.20636

Cited by 195 publications

(147 citation statements)

References 14 publications

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“…Mutations in LRKK2 are the most common genetic cause of autosomal dominant PD to date, resulting in about 2 % of all cases of PD [136,137] and up to 40 % in some isolated populations, such as those in North African regions [138,139]. LRRK2 is a large multidomain protein that contains serine/threonine kinase activity.…”

Section: Kinase Inhibitorsmentioning

confidence: 99%

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

2014

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Parkinson disease is an inexorably progressive neurodegenerative disorder. Multiple attempts have been made to establish therapies for Parkinson disease which provide neuroprotection or disease modification-two related, but not identical, concepts. However, to date, none of these attempts have succeeded. Many challenges exist in this field of research, including a complex multisystem disorder that includes dopaminergic and non-dopaminergic features; poorly understood and clearly multifaceted disease pathogenic mechanisms; a lack of reliable animal models; an absence of effective biomarkers of disease state, progression, and target engagement; and the confounding effects of potent symptomatic therapy. In this article, we will review previous, ongoing, and potential future trials designed to alter the progressive course of the disease from the perspective of the targeted underlying pathogenic mechanisms.

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Section: Kinase Inhibitorsmentioning

confidence: 99%

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

2014

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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

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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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“…70 A second study found the penetrance to be 33% at age 55 and 100% by age 75. 74 However, it is quite likely that the estimated penetrance of the G2019S mutation is greater in pedigrees with autosomal dominant inheritance as compared with estimates from pedigrees without such a strong family history of disease. Therefore, to avoid an ascertainment bias, a recent study ascertained LRRK2 mutation carriers through the molecular screening of a large series of consecutive PD patients who were tested regardless of their family history of PD.…”

Section: Park8: Lrrk2mentioning

confidence: 99%

Genetics of Parkinson disease

Pankratz

Foroud

2007

Genetics in Medicine

109

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During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease. Thus, researchers have continued to search for genes that may influence disease susceptibility. Molecular diagnostic testing is currently available for four of the genes mutated in Parkinson disease. Evidence for reduced penetrance, possible effects of haploinsufficiency, and the identification of nondisease causing polymorphisms within several of these genes has made genetic counseling challenging.Current recommendations are to limit molecular testing only to those individuals who are symptomatic. Furthermore, because treatment is unaltered by the presence or absence of mutations in these genes, restraint is recommended when considering the value of screening for mutations in a clinical setting. Genet Med 2007:9(12): 801-811.

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G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Cited by 195 publications

References 14 publications

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

Pathogenesis-Targeted, Disease-Modifying Therapies in Parkinson Disease

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

Genetics of Parkinson disease

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