Confirmation of the association between LRRK2 R1628P variant and susceptibility to Parkinson's disease in the Thai population

Pulkes, Teeratorn; Papsing, Chutima; Thakkinstian, Ammarin; Pongpakdee, Sunsanee; Kulkantrakorn, Kongkiat; Hanchaiphiboolkul, Suchat; Tiamkao, Somsak; Boonkongchuen, Pairoj

doi:10.1016/j.parkreldis.2014.06.013

Cited by 14 publications

(12 citation statements)

References 12 publications

(22 reference statements)

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“…The G2385R and R1628P variants of LRRK2 are particularly frequent in the Asian population, where they cause a 2- to 3-fold increased risk for PD (Wu et al 2013; Gopalai et al 2014). With a frequency of 3–5% in the Asian PD population, these two variants can be considered as the most common variants for developing PD in East Asia (Pulkes et al 2014). …”

Section: Genetic Risk Factors Linked To Impaired Mitochondrial Functimentioning

confidence: 99%

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

2018

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Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17–23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

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Section: Genetic Risk Factors Linked To Impaired Mitochondrial Functimentioning

confidence: 99%

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

2018

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“…Rare variation was detected in LRRK2 and SMPD1 (Table 4), where we found five nonsynonymous variants that were present in patients but not in Finnish ExAC controls. Two variants were deemed to be deleterious (Table 4) and, interestingly, the p.R542Q variant in SMPD1 was homozygous and the p.R1628P in LRRK2 has previously been reported in association with PD [18]. …”

Section: Resultsmentioning

confidence: 99%

“…PredictSNP suggested that the LRRK2 variant p.R1628P is deleterious. This variant has been previously associated with PD in Chinese and Thai populations [18]. The p.R1628P variant acts by turning its adjacent amino acid residue S1627 to a new phosphorylation site of Cdk5.…”

Section: Discussionmentioning

confidence: 99%

Genetic risk factors in Finnish patients with Parkinson's disease

Ylönen

Siitonen

Nalls

et al. 2017

Parkinsonism & Related Disorders

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Introduction Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. Methods The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). Results We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. Conclusions The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.

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“…16 Similarly, the R1628P, A419V variants were associated with PD in Asian cohorts, whereas the M1646 T conferred risk in whites. 4,8,17,18 In a large East Asian cohort assessing nonsynonymous coding variations in the known PD genes, only variations in the LRRK2 were found to be enriched in PD patients. 19,20 Population-specific differences in the minor allele frequencies of the LRRK2 variants may contribute toward the relative significance of a particular variant in genetically diverse populations.…”

Section: Lrrk2mentioning

confidence: 99%

Understanding the role of genetic variability in LRRK2 in Indian population

et al. 2018

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Background Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. Objectives To resolve the role of LRRK2 in the Indian population. Methods We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. Results We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild‐type, the kinase domain variant showed 4‐fold increase in the kinase activity. Conclusions Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society

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Confirmation of the association between LRRK2 R1628P variant and susceptibility to Parkinson's disease in the Thai population

Cited by 14 publications

References 12 publications

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

Genetic risk factors in Finnish patients with Parkinson's disease

Understanding the role of genetic variability in LRRK2 in Indian population

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