LRRK2 G2019S mutation and Parkinson's disease: A clinical, neuropsychological and neuropsychiatric study in a large Italian sample

Goldwurm, Stefano; Zini, Michela; Fonzo, Alessio Di; Gaspari, Danilo De; Siri, Chiara; Simons, Erik J.; Doeselaar, Marina van; Tesei, Silvana; Antonini, Angelo; Canesi, Margherita; Zecchinelli, Anna; Mariani, Claudio; Meucci, N.; Sacilotto, Giorgio; Cilia, Roberto; Isaias, Ioannis U.; Bonetti, Alba; Sironi, Francesca; Ricca, Sara; Oostra, Ben A.; Bonifati, Vincenzo; Pezzoli, Gianni

doi:10.1016/j.parkreldis.2006.04.001

Cited by 101 publications

(88 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even when confined to LRRK2 G2019S, penetrance estimates vary widely (24%-100%). 8 Penetrance estimates may differ based on ethnic group, sex, and the presence of genetic or environmental modifiers of age at onset. How probands and family members are ascertained and the statistical methodologies used may also help explain this range in estimates; for example, 8 young-onset and familial cases, both of whom are more likely to harbor genetic mutations, are more likely to be seen at an academic center.…”

mentioning

confidence: 99%

“…8 Penetrance estimates may differ based on ethnic group, sex, and the presence of genetic or environmental modifiers of age at onset. How probands and family members are ascertained and the statistical methodologies used may also help explain this range in estimates; for example, 8 young-onset and familial cases, both of whom are more likely to harbor genetic mutations, are more likely to be seen at an academic center. Here, we estimate penetrance of LRRK2 G2019S in a genetically homogenous AJ cohort, using the same validated family history interview (FHI) at 3 academic centers specialized in the care of PD.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

View full text Add to dashboard Cite

Objective: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. Methods:The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.Results: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p , 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p 5 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p , 0.001). Conclusion:Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted. Neurology ® 2015;85:89-95 GLOSSARY AJ 5 Ashkenazi Jewish; CI 5 confidence interval; FHI 5 family history interview; GBA 5 glucocerebrosidase; HR 5 hazard ratio; PD 5 Parkinson disease.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

et al. 2015

View full text Add to dashboard Cite

show abstract

“…LRRK2 is a complex 286-kDa protein that consists of multiple domains, including (in order, from the amino to carboxyl terminus) armadillo, ankyrin, and the namesake leucine-rich repeats (LRRs), followed by an ROC (Ras of complex proteins) GTPase domain, a COR (C-terminal of ROC) dimerization domain, a kinase domain, and a predicted C-terminal WD40 repeat domain (4-6). Several single-nucleotide alterations have been identified in LRRK2, but only five missense mutations within the ROC, COR, and kinase domains clearly segregate with PD in large family studies (7,8). It has recently been shown that the WD40 domain is required to stabilize the LRRK2 dimer and to execute LRRK2-associated kinase activity as well as neurotoxicity (9, 10), but the role of this domain within LRRK2 physiological and pathological function has not yet been completely defined.…”

mentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

Piccoli

Onofri

Cirnaru

et al. 2014

Molecular and Cellular Biology

108

View full text Add to dashboard Cite

jMutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of the purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicles via interaction with vesicle-associated proteins. In fact, a domain-based pulldown approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of the WD40 domain within LRRK2 function. Parkinson's disease (PD) is the second most common age-related neurodegenerative disease and is clinically characterized by movement impairments, bradykinesia, rigidity, and resting tremor and pathologically by the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (1, 2). Although the majority of cases are sporadic, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene (PARK8; Online Mendelian Inheritance in Man [OMIM] accession number 609007) had been unequivocally linked to late-onset autosomal dominant PD. LRRK2 mutations account for up to 13% of familial PD cases compatible with dominant inheritance and are also found in 1 to 2% of sporadic PD patients (62-64). LRRK2 is a complex 286-kDa protein that consists of multiple domains, including (in order, from the amino to carboxyl terminus) armadillo, ankyrin, and the namesake leucine-rich repeats (LRRs), followed by an ROC (Ras of complex proteins) GTPase domain, a COR (C-terminal of ROC) dimerization domain, a kinase domain, and a predicted C-terminal WD40 repeat domain (4-6). Several single-nucleotide alterations have been identified in LRRK2, but only five missense mutations within the ROC, COR, and kinase domains clearly segregate with PD in large family studies (7,8). It has recently been shown that the WD40 domain is required to stabilize the LRRK2 dimer and to execute LRRK2-associated kinase activity as well as neurotoxicity (9, 10), but the role of this domain within LRRK2 physiological and pathological function has not yet been completely defined. The beta-propellerforming WD40 domains are among the 10 most abundant domain types across eukaryotic proteomes (11) and constitute platforms where multiprotein complexes assemble reversibly (12). Here, we systematically analyzed the protein-protein interactions conferred by the LRRK2 WD40 domain. The nature of the LRRK2 WD40 interactors and the finding that the LRRK2 WD40 domain is able to bind to synaptic...

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

LRRK2 G2019S mutation and Parkinson's disease: A clinical, neuropsychological and neuropsychiatric study in a large Italian sample

Cited by 101 publications

References 46 publications

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Age-specific penetrance ofLRRK2G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

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

Contact Info

Product

Resources

About