Clinical heterogeneity of the LRRK2 G2019S mutation

University of Miami, كورال غيبلز، فلوريدا, Florida, United States
JAMA Neurology (Impact Factor: 7.42). 10/2006; 63(9):1242-6. DOI: 10.1001/archneur.63.9.1242
Source: PubMed


Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene (LRRK2) that cause parkinsonism. The "common" LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease.
To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers.
We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T.
Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations.
Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants.
The underlying disease mechanisms of LRRK2 G2019S-associated parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.

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Available from: Owen A Ross, Jan 17, 2014
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    • "As PD is considered a multifactorial disease, multiple genetic and environmental factors may interact to induce dopaminergic neuron death [37]. Indeed, varied disease penetrance and varied onset time are observed in the subjects carrying pathogenic mutation in LRRK2 [9], favoring multifactorial pathogenesis in PD. Mutation of a single PD gene, particularly with low yield, may not be sufficient to induce neuron death within the short lifespan of rodents. "
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    ABSTRACT: Parkinson's disease (PD) results from progressive degeneration of dopaminergic neurons. Most PD cases are sporadic, but some have pathogenic mutation in the individual genes. Mutation of the leucine-rich repeat kinase-2 (LRRK2) gene is associated with familial and sporadic PD, as exemplified by G2019S substitution. While constitutive expression of mutant LRRK2 in transgenic mice fails to induce neuron death, transient expression of the disease gene by viral delivery causes a substantial loss of dopaminergic neurons in mice. To further assess LRRK2 pathogenesis, we created inducible transgenic rats expressing human LRRK2 with G2019S substitution. Temporal overexpression of LRRK2(G2019S) in adult rats impaired dopamine reuptake by dopamine transporter (DAT) and thus enhanced locomotor activity, the phenotypes that were not observed in transgenic rats constitutively expressing the gene throughout life time. Reduced DAT binding activity is an early sign of dopaminergic dysfunction in asymptomatic subjects carrying pathogenic mutation in LRRK2. Our transgenic rats recapitulated the initiation process of dopaminergic dysfunction caused by pathogenic mutation in LRRK2. Inducible transgenic approach uncovered phenotypes that may be obscured by developmental compensation in constitutive transgenic rats. Finding in inducible LRRK2 transgenic rats would guide developing effective strategy in transgenic studies: Inducible expression of transgene may induce greater phenotypes than constitutive gene expression, particularly in rodents with short life time.
    International journal of biological sciences 06/2011; 7(6):753-61. · 4.51 Impact Factor
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    • "nonpathogenic (Table 3); however, three LRRK2 variants, p.Arg1628Pro, p.Gly2019Ser, and p.Gly2385Arg, are exceptions to this last point. The p.Gly2019Ser mutation, although absent in more than 10,000 control individuals reported to date [Carmine Belin et al., 2006; Lesage et al., 2006; Ozelius et al., 2006; Papapetropoulos et al., 2006; Ross et al., 2006; Zabetian et al., 2006a], has also been identified in some asymptomatic individuals (16), of which one was 89 years old [Kay et al., 2005]. In addition, four clinically unaffected individuals of Algerian and Tunisian origin were found to be homozygous p.Gly2019Ser carriers (ages 41, 42, 45, and 70 years) [Ishihara et al., 2006; Lesage et al., 2008]. "
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    ABSTRACT: Mutation in the LRRK2 gene is a known genetic cause of Parkinson disease (PD). However, due to the high frequency in which the most frequent LRRK2 mutation is present and the large size of LRRK2 gene, a complete sequence-based screening of the entire coding region has only been performed by a few researchers. In addition, normal variability in the LRRK2 gene has only been fully assessed in the North American population. Although a complete examination of the entire gene is required to assess the exact contribution of LRRK2 to the etiology of PD, more than 50 variants have been reported to date within the LRRK2 locus. Gene multiplications or deletions have not been reported so far. Here, all LRRK2 variants reported are interpreted and their contribution to the disease is examined.
    Human Mutation 05/2009; 30(8):1153-60. DOI:10.1002/humu.21038 · 5.14 Impact Factor
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    • "The original Japanese family carries an isoleucine to threonine substitution at position 2020 (I2020T) in the kinase domain (Funayama et al., 2005). The common mutation found in many families worldwide is a glycine to serine change at the adjacent residue (G2019S) (Gilks et al., 2005; Goldwurm et al., 2005; Lesage et al., 2005; Infante et al., 2006; Marongiu et al., 2006; Pankratz et al., 2006; Papapetropoulos et al., 2006; Saunders-Pullman et al., 2006; Williams-Gray et al., 2006; Zabetian et al., 2006a, 2006b; Ishihara et al., 2007; Orr-Urtreger et al., 2007; Gorostidi et al., 2008; Healy et al., 2008; Latourelle et al., 2008; Munhoz et al., 2008). In the ROC domain, an arginine at residue 1441 can be replaced by a glycine residue (R1441G) in several families in Spain and Portugal (Paisán-Ruíz et al., 2004; Mata et al., 2005; Ferreira et al., 2007; Bras et al., 2008; Gorostidi et al., 2008) or by a cysteine residue (R1441C) in a family from Nebraska (Zimprich et al., 2004b; Haugarvoll et al., 2008). "
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    ABSTRACT: Mutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein-protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we discuss the evidence of LRRK2 activity as a GTPase and as a kinase and the available data on protein-protein interactions. Next we raise the question of how mutations affect LRRK2 function, focusing on some slightly controversial results related to the kinase activity of the protein in a variety of in vitro systems. Finally, we discuss what the possible mechanisms are for LRRK2-mediated neurotoxicity, in the context of known activities of the protein.
    ASN Neuro 02/2009; 1(1). DOI:10.1042/AN20090007 · 4.02 Impact Factor
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