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

Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, 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.

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    • "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]. "
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    • "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. "
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    • "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)]. "
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