Leucine-rich repeat kinase 2 (mutations in 3 frequently reported exons (31,

Leucine-rich repeat kinase 2 (mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). and p.R1441G/C/H are frequent mutations in and the prevalence of the p.G2019S mutation, the most common substitution in populations of European origin, is estimated at 5%-13% of individuals with familial PD (Haugarvoll and Wszolek, 2009), the p.R1441C, p.R1441H, and p.G2019S mutations have been found to be very rare in Asia (Haugarvoll et al., 2008; Ross et al., 2009). The p.R1441G mutation is frequent in Spain, and especially in the Basque country, where it accounts for 16% of familial and 4% of sporadic cases (Haugarvoll and Wszolek, 2009). However, p.R1441G carriers are Salinomycin extremely rare outside of Spain (Haugarvoll and Wszolek, 2009; Mata et al., 2005, 2009b; Simon-Sanchez et al., 2006). To date, only 4 probands with p.R1441G outside of northern Spain have been reported (Cornejo-Olivas et al., 2013; Deng et al., 2006; Mata et al., 2009a; Yescas et al., 2010). Interestingly, most of the reported p.R1441G PD patients share a common founder, and this mutation is regarded Salinomycin as a rare haplotype (Haugarvoll and Wszolek, 2009; Rabbit Polyclonal to HSP60 Mata et al., 2005, 2009b; Simon-Sanchez et al., 2006). It remains unclear whether there are patients carrying the p.R1441G mutation in Asia. In this study, we performed a mutation screening of exons 31, 41, and 48 of in a Japanese cohort of PD patients and found a proband with the p.R1441G mutation. Here, we report the results of a clinicoradiological and haplotype analysis of the first familial PD patients linked to p.R1441G mutation in Asian countries. 2. METHODS 2.1. Subjects We studied 871 Japanese PD patients (430 patients with sporadic PD and 441 probands with familial PD; age, 56.4 14.5 years; age at onset, 49.8 14.6 years; disease duration; 6.67 6.89 years). A clinical diagnosis of PD was determined by the presence of at least 2 of 3 cardinal signs (rest tremor, bradykinesia, and rigidity) and improvement following adequate Salinomycin dopaminergic therapy (when available). In this study, families with 2 or more affected members or 2 members with a mutation in at least 2 generations were classified as autosomal dominant PD families, and families with Salinomycin at least 2 affected siblings in only 1 generation were classified as (potential or pseudo-) autosomal recessive PD families. Written informed consent was obtained from all participants, and the local ethics authorities approved the project. A 2-generation pedigree was established for the Japanese family with the LRRK2 p.R1441G mutation (Fig. 1A). Among the 12 subjects in the family, 4 (II:5, II:4, I:6, and II:2) were willing to participate in this clinicogenetic study, whereas the remainder, including 2 reportedly parkinsonian subjects (I:2 and I:3), refused to participate. Participating individuals were examined by neurologists specializing in movement disorders. A full history was collected and a neurologic examination was performed for each patient. Figure. 1 Pedigree and direct sequencing analysis of the Japanese family with the p.R1441G mutation 2.2. Genetic analysis Genomic DNA from each subject was extracted from peripheral blood using the QIA amp DNA Blood Maxi Kit (QIAGEN, Valencia, CA, USA). Three exons of LRRK2 that have been frequently reported to contain PD-associated mutations (exons 31, 41, and 48) were analyzed by polymerase chain reaction-direct sequencing using the Big Dye Terminator v.1.1 Cycle Sequencing Kit (Life Technologies, Foster City, CA, USA) as previously described (Zimprich et al., 2004). Haplotype analysis of LRRK2 flanking region was performed using previously described methods (Mata et al., 2005, 2009a, 2009b). 3. RESULTS 3.1 Genetic Findings In this cohort, we identified 1 proband (0.11%) with a p.R1441G mutation, 1 with a p.G2019S mutation (0.11%), and 103 with a p.G2385R variant (11.37%).We failed to detect p.R1441C, p.R1441H, or p.I2020T mutations in this cohort. The pedigree of the family with the p.R1441G mutation is shown in Fig.1A. Five members of this family presented with parkinsonism (I:2, I:3, I:6, II:2, and II:5). Direct sequencing analysis of revealed a heterozygous p.R1441G (4321C>G) mutation in II:5 (proband), I:6, and II:2. A healthy brother (II:4) of the proband did not share the mutation (Fig. 1B). Two individuals (II:2: a first cousin of the proband with the p.R1441G mutation, 50-year-old female; and II:4: a healthy brother of the proband without the p.R1441G mutation, 35-year-old male) were heterozygous for the p.G2385R (7153G>A) variant, which was observed on a different haplotype to that in individuals with the p.R1441G.

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