Genotype-phenotype correlation of Parkinson's disease with PRKN variants

Yoshino, Hideaki; Li, Yuanzhe; Nishioka, Kenya; Daida, Kensuke; Hayashida, Arisa; Ishiguro, Yuta; Yamada, Daisuke; Izawa, Nana; Nishikawa, Noriko; Oyama, Genko; Hatano, Taku; Nakamura, Shinichiro; Yoritaka, Asako; Motoi, Yumiko; Funayama, Manabu; study, the investigators of Japan Parkinson disease genetic

doi:10.1016/j.neurobiolaging.2021.12.014

Cited by 23 publications

(24 citation statements)

References 61 publications

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“…The two known mutants on PLA2G6 p.Ala80Thr and VPS35 p.Asp620Asn were identified in our cohort with the frequency of 1.2% (one out of 83 for each) presented similar characteristics as previously reported (Agarwal et al., 2012 , Magrinelli et al., 2022 ; Yoshino et al., 2022 ), except the early age at onset.…”

Section: Discussionsupporting

confidence: 87%

Clinical and genetic analysis of Vietnamese patients diagnosed with early‐onset Parkinson's disease

Tran

Luong

et al. 2023

Brain and Behavior

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Background Genetic factors play a crucial role in the pathogenesis of Parkinson's disease (PD). However, no comprehensive study has described genetic alterations in Vietnamese patients diagnosed with PD. This study aimed to identify genetic causes and their association with clinical phenotypes in a Vietnamese PD cohort. Methods A total of 83 patients with early‐onset PD (disease onset before the age of 50) were recruited for genetic analysis using a combination of multiplex ligation‐dependent probe amplification and next‐generation sequencing for a panel of 20 PD‐associated genes. Results It was found that 37 out of 83 patients carried genetic alterations, with 24 pathogenic/likely pathogenic/risk variants and 25 variants of uncertain significance. The pathogenic/likely pathogenic/risk variants were mostly detected in LRRK2 , PRKN , and GBA , while the variants of uncertain significance were identified in 12 different genes that were studied. The most common genetic alteration was LRRK2 c.4883G>C (p.Arg1628Pro), and patients with PD carrying this variant were found to have a distinct phenotype. Participants carrying pathogenic/likely pathogenic/risk variants had a significantly higher rate of a family history of PD. Conclusion These results provide a further understanding of genetic alterations associated with PD in a South‐East Asian population.

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Section: Discussionsupporting

confidence: 87%

Clinical and genetic analysis of Vietnamese patients diagnosed with early‐onset Parkinson's disease

Tran

Luong

et al. 2023

Brain and Behavior

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“…The most frequent causative gene of PD in Japan is the PRKN gene, which is the causative gene of autosomal recessive juvenile PD, as reported by Kitada et al in 1998 [ 3 ]. We recently published the results of a study of the PRKN gene in over 2000 cases, and identified biallelic variants in PRKN that are observed in 8.1% (98/1204) of familial PD and 5.8% (65/1118) of sporadic PD cases [ 5 ]. It is important to note that this population included many patients who were clinically diagnosed as likely to have PRKN variants and were actively selected for genetic analysis.…”

Section: Molecular Genetics Of Mendelian Forms Of Pdmentioning

confidence: 99%

“…We also found PD patients with a putative pathogenic monoallelic rare variant in the PRKN gene, with a frequency of 2.5% (57/2322). A comparison of clinical symptoms between the biallelic and monoallelic variants showed that the age at onset was 29.6 ± 9.8 years for the biallelic variants and 45.2 ± 15.9 years for the monoallelic variant, which indicates an earlier age of onset for the biallelic variants [ 5 ]. Additionally, more cases of Hoehn and Yahr stage IV or V were observed in the biallelic variants in patients who had the disease for at least 15 years [ 5 ].…”

Section: Molecular Genetics Of Mendelian Forms Of Pdmentioning

confidence: 99%

“…A comparison of clinical symptoms between the biallelic and monoallelic variants showed that the age at onset was 29.6 ± 9.8 years for the biallelic variants and 45.2 ± 15.9 years for the monoallelic variant, which indicates an earlier age of onset for the biallelic variants [ 5 ]. Additionally, more cases of Hoehn and Yahr stage IV or V were observed in the biallelic variants in patients who had the disease for at least 15 years [ 5 ]. The PRKN gene is the causative gene of autosomal recessive juvenile PD, and therefore, a person with a monoallelic variant is presumed to be an unaffected carrier.…”

Section: Molecular Genetics Of Mendelian Forms Of Pdmentioning

confidence: 99%

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Molecular genetics of Parkinson’s disease: Contributions and global trends

Funayama

Nishioka

2022

J Hum Genet

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Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by motor dysfunction. Aging is the greatest risk factor for developing PD. Recent molecular genetic studies have revealed that genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Studies of familial PD have identified approximately 20 different causative genes. PRKN is the most frequently detected causative gene in Japan. The PRKN gene is located at a common fragile site, and both copy number variants as well as single nucleotide variants are frequently detected. The location and variety of variant types makes an accurate genetic diagnosis difficult with conventional genetic testing. In sporadic PD, genome-wide association studies have revealed more than 200 genes that are potential drivers for the development of PD. Many of these studies have been conducted in Caucasian populations alone, which has limited the identification of all genetic risk factors for sporadic PD, particularly as genetic backgrounds vary widely by race. The Global Parkinson’s Genetics Program is a global undertaking meant to address the issue of regional differences in genetic studies of PD.

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“…Most of the genes (e.g. Dpysl, Prkn, Gls) that were associated with ex vivo radiosensitivity have systemic functions in regulating oxidative stress, mitochondrial functions and carcinogenesis (WANG et al 2010;MATSUNUMA et al 2018;KANG et al 2019), in addition to their involvement in neurodegeneration (MANIVANNAN et al 2013;LYNCH et al 2018;YOSHINO et al 2022). The variety of functions might explain why these genes were identified in fibroblast radiation responses ex vivo and suggests them as peripheral biomarkers of neurological risk for future experimental validation.…”

Section: Comparing Responses To High and Low Let Radiationmentioning

confidence: 99%

Mouse Genomic Associations withEx VivoSensitivity to Simulated Space Radiation

Cekanaviciute

Tran

Nguyen

et al. 2022

Preprint

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Exposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-induced ex vivo DNA damage quantified based on immunofluorescent 53BP1+ nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 hour) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1+ foci as a potential biomarker for DNA integrity in mouse models. Based on our results, we suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future human ex vivo studies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.

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Genotype-phenotype correlation of Parkinson's disease with PRKN variants

Cited by 23 publications

References 61 publications

Clinical and genetic analysis of Vietnamese patients diagnosed with early‐onset Parkinson's disease

Clinical and genetic analysis of Vietnamese patients diagnosed with early‐onset Parkinson's disease

Molecular genetics of Parkinson’s disease: Contributions and global trends

Mouse Genomic Associations withEx VivoSensitivity to Simulated Space Radiation

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