The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor

Department of Neurological Sciences, University of Milan, Milano, Lombardy, Italy
Journal of Medical Genetics (Impact Factor: 6.34). 11/2005; 42(11):e65. DOI: 10.1136/jmg.2005.035568
Source: PubMed


Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease.
To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease.
Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years).
G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.

Download full-text


Available from: Angelo Antonini
  • Source
    • "R1441G/C/H mutations map to the ROC domain [4,7,8], Y1669C to the COR domain [1], and I2020T and G2019S mutations to the kinase domain [9,10]. In this frame, the G2019S mutation is by far the most common pathogenic LRRK2 mutation, and is responsible for more than 10% of familial PD cases and 1 to 2% of sporadic PD cases [11]. Several studies have shown that of all the LRRK2 mutations, only the G2019S mutation consistently increases kinase activity [12-14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is now well established that chronic inflammation is a prominent feature of several neurodegenerative disorders including Parkinson's disease (PD). Growing evidence indicates that neuroinflammation can contribute greatly to dopaminergic neuron degeneration and progression of the disease. Recent literature highlights that leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in both autosomal-dominantly inherited and sporadic PD cases, modulates inflammation in response to different pathological stimuli. In this review, we outline the state of the art of LRRK2 functions in microglia cells and in neuroinflammation. Furthermore, we discuss the potential role of LRRK2 in cytoskeleton remodeling and vesicle trafficking in microglia cells under physiological and pathological conditions. We also hypothesize that LRRK2 mutations might sensitize microglia cells toward a pro-inflammatory state, which in turn results in exacerbated inflammation with consequent neurodegeneration.
    Full-text · Article · Mar 2014 · Journal of Neuroinflammation
  • Source
    • "Dominant mutations in LRRK2 are the most common cause of familial PD (Goldwurm et al. 2005). Structurally, LRRK2 is a very interesting protein, which has GTPase and kinase domains in addition to leucine-rich repeat domains, forming a large protein kinase. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed.
    Full-text · Article · Sep 2012 · Cold Spring Harbor Perspectives in Medicine
  • Source
    • "Few LRRK2 substrates, including moesin, 4E-BP, MKKs, tubulin beta, and a-synuclein, have been found so far in in vitro assays (Jaleel et al. 2007; Imai et al. 2008; Gillardon 2009; Gloeckner et al. 2009; Qing et al. 2009). Several single nucleotide alterations have been identified in LRRK2 (Lesage et al. 2005; Mata et al. 2005), covering all functional domains, but only five missense mutations clearly segregate with PD in large family studies (Goldwurm et al. 2005; Bonifati 2006a, b). Disease-segregating mutations in LRRK2 have been reported in the kinase domain (G2019S, I2020T), in the Roc domain (R1441C/G), and in the COR domain (Y1699C) [reviewed in Mata et al. (2005)]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activity-dependent modifications in synaptic efficacy, such as long-term depression (LTD) and long-term potentiation (LTP), represent key cellular substrates for adaptive motor control and procedural memory. The impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson’s disease (PD), characterized by the massive degeneration of dopaminergic neurons. In fact, both LTD and LTP are peculiarly controlled and modulated by dopaminergic transmission coming from nigrostriatal terminals. Changes in corticostriatal and nigrostriatal neuronal excitability may influence profoundly the threshold for the induction of synaptic plasticity, and changes in striatal synaptic transmission efficacy are supposed to play a role in the occurrence of PD symptoms. Understanding of these maladaptive forms of synaptic plasticity has mostly come from the analysis of experimental animal models of PD. A series of cellular and synaptic alterations occur in the striatum of experimental parkinsonism in response to the massive dopaminergic loss. In particular, dysfunctions in trafficking and subunit composition of glutamatergic NMDA receptors on striatal efferent neurons contribute to the clinical features of the experimental parkinsonism. Interestingly, it has become increasingly evident that in striatal spiny neurons, the correct assembly of NMDA receptor complex at the postsynaptic site is a major player in early phases of PD, and it is sensitive to distinct degrees of DA denervation. The molecular defects at the basis of PD progression may be not confined just at the postsynaptic neuron: accumulating evidences have recently shown that the genes linked to PD play a critical role at the presynaptic site. DA release into the synaptic cleft relies on a proper presynaptic vesicular transport; impairment of SV trafficking, modification of DA flow, and altered presynaptic plasticity have been described in several PD animal models. Furthermore, an impaired DA turnover has been described in presymptomatic PD patients. Thus, given the pathological events occurring precociously at the synapses of PD patients, post- and presynaptic sites may represent an adequate target for early therapeutic intervention.
    Full-text · Article · Jan 2012 · Advances in Experimental Medicine and Biology
Show more