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

Goldwurm, Stefano; Fonzo, Alessio Di; Simons, Erik J.; Rohé, Christan F.; Zini, Michela; Canesi, Margherita; Tesei, Silvana; Zecchinelli, Anna; Antonini, Angelo; Mariani, Claudio; Meucci, N.; Sacilotto, Giorgio; Sironi, Francesca; Salani, Giuliana; Ferreira, João Boavida; Chien, Hsin Fen; Fabrizio, Edito; Vanacore, Nicola; Libera, A. Dalla; Stocchi, Fabrizio; Diroma, Cosimo; Lamberti, Paolo; Sampaio, Cristina; Meco, Giuseppe; Barbosa, Egberto Reis; Bertoli‐Avella, Aida M.; Breedveld, Guido J.; Oostra, Ben A.; Pezzoli, Gianni; Bonifati, Vincenzo

doi:10.1136/jmg.2005.035568

Cited by 174 publications

(151 citation statements)

References 20 publications

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“…The p.G2019S and p.R1441C mutations were previously shown to be absent in more than 800 and 500 Italian control chromosomes, respectively. 27 On the contrary, one heterozygous carrier of the p.I1371V mutation was detected in this study among 416 Italian control chromosomes (allelic frequency 0.002).…”

Section: Genetic Studiescontrasting

confidence: 52%

“…Haplotypes were constructed manually. We included in the haplotype analysis the two families with the p.R1441C mutation detected in this study, a further PD family carrying this mutation detected by us in a different sample set, 27 as well as family 'D' (from Western Nebraska) and family '469', in which the p.R1441C mutation was initially identified. 9 The phase could be assigned unambiguously in family 'D' by typing a trio of parents/child.…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

et al. 2005

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Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

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Section: Genetic Studiescontrasting

confidence: 52%

Section: Methodsmentioning

confidence: 99%

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

et al. 2005

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“…11 In addition, the discovery of G2019S established for the first time the proof-of-principle for a genetic determinant frequently involved in sporadic PD. 7,8,12 The evidence that G2019S is pathogenic is overwhelming. This mutation is very frequent in PD and extremely rare in controls, 5 -8,12 and it cosegregates with PD in large families.…”

mentioning

confidence: 99%

“…6,8,13 The G2019 residue is extremely conserved in LRRK2 homologs and the mutation increases the kinase activity of the protein. 14 However, the prevalence of G2019S is population specific: very rare in Asia, 15 low in Northern Europe, 8 and high in Italy, 12 Spain 16 and Portugal. 17 Haplotype analyses revealed that all carriers of this mutation inherited the same ancestral chromosome.…”

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Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics

Bonifati

2006

Eur J Hum Genet

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Clinical Features of Parkinson Disease Patients With Homozygous Leucine-Rich Repeat Kinase 2 G2019S Mutations

Ishihara¹,

Warren²,

Gibson³

et al. 2006

Arch Neurol

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Background: The G2019S mutation is the most common pathogenic substitution in the leucine-rich repeat kinase 2 (LRRK2) gene, which has recently been identified in familial and sporadic Parkinson disease (PD). Objectives: To report the clinical characteristics of PD patients with homozygous LRRK2 6055GϾA (G2019S) mutations and to compare them with previously published descriptions of heterozygous patients. Design: Descriptive clinical report from an international consortium of studies. Subjects: Patients with familial PD and homozygous LRRK2 mutations included 23 Tunisians, 2 Algerians, 2 US patients, 1 Canadian, and 1 Moroccan. Results: There were no observable differences between the homozygote and heterozygote phenotypes. Conclusions: Parkinson disease related to LRRK2 is characterized by typical clinical features, and the similarities between patients with homozygous and heterozygous mutations do not support a gene dosage effect.

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

Cited by 174 publications

References 20 publications

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics

Clinical Features of Parkinson Disease Patients With Homozygous Leucine-Rich Repeat Kinase 2 G2019S Mutations

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