Prevalence and Phenotypic Spectrum of PINK1 Mutations in Parkinson’s Disease

2009 ◽  
Vol 4 (1) ◽  
pp. 40 ◽  
Author(s):  
Alessandro Ferraris ◽  
Enza Maria Valente ◽  
Anna Rita Bentivoglio ◽  
◽  
◽  
...  

Several genes have been identified as causative of autosomal dominant or recessive forms of Parkinson’s disease (PD). Bi-allelic mutations in the phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) gene represent the second most frequent cause of autosomal recessive parkinsonism (ARP) after PARK2/Parkin. The typicalPINK1-associated phenotype is characterised by early age at onset, slow disease progression and excellent and sustained response to levodopa, but in rare cases the clinical presentation can be indistinguishable from that of sporadic PD. Single heterozygous rare variants in thePINK1gene, as well as in other ARP genes, have been frequently detected both in parkinsonian patients and in healthy controls. Although their pathogenetic role is still debated, these variants have been suggested to act as minor risk factors for developing PD.

US Neurology ◽  
2009 ◽  
Vol 05 (01) ◽  
pp. 34 ◽  
Author(s):  
Alessandro Ferraris ◽  
Enza Maria Valente ◽  
Anna Rita Bentivoglio ◽  
◽  
◽  
...  

Several genes have been identified as causative of autosomal dominant or recessive forms of Parkinson’s disease (PD). Bi-allelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene represent the second most frequent cause of autosomal recessive parkinsonism (ARP) after PARK2/Parkin. The typicalPINK1-associated phenotype is characterized by early age at onset, slow disease progression, and excellent and sustained response to levodopa, but in rare cases the clinical presentation can be indistinguishable from that of sporadic PD. Single heterozygous rare variants in thePINK1gene, as well as in other ARP genes, have been frequently detected both in parkinsonian patients and in healthy controls. Although their pathogenetic role is still debated, these variants have been suggested to act as minor risk factors for developing PD.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jianshe Wei ◽  
Gilbert Ho ◽  
Yoshiki Takamatsu ◽  
Eliezer Masliah ◽  
Makoto Hashimoto

The majority of Parkinson’s disease (PD) is sporadic in elderly and is characterized by α-synuclein (αS) aggregation and other alterations involving mitochondria, ubiquitin-proteasome, and autophagy. The remaining are familial PD associated with gene mutations of either autosomal dominant or recessive inheritances. However, the former ones are similar to sporadic PD, and the latter ones are accompanied by impaired mitophagy during the reproductive stage. Since no radical therapies are available for PD, the objective of this paper is to discuss a mechanistic role for amyloidogenic evolvability, a putative physiological function of αS, among PD subtypes, and the potential relevance to therapy. Presumably, αS evolvability might benefit familial PD due to autosomal dominant genes and also sporadic PD during reproduction, which may manifest as neurodegenerative diseases through antagonistic pleiotropy mechanism in aging. Indeed, there are some reports describing that αS prevents apoptosis and mitochondrial alteration under the oxidative stress conditions, notwithstanding myriads of papers on the neuropathology of αS. Importantly, β-synuclein (βS), the nonamyloidogenic homologue of αS, might buffer against evolvability of αS protofibrils associated with neurotoxicity. Finally, it is intriguing to predict that increased αS evolvability through suppression of βS expression might protect against autosomal recessive PD. Collectively, further studies are warranted to better understand αS evolvability in PD pathogenesis, leading to rational therapy development.


Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2220-2234 ◽  
Author(s):  
Yuwen Zhao ◽  
Lixia Qin ◽  
Hongxu Pan ◽  
Zhenhua Liu ◽  
Li Jiang ◽  
...  

Abstract This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.


2020 ◽  
Author(s):  
Yongping Chen ◽  
Xiaojing Gu ◽  
Ruwei Ou ◽  
Lingyu Zhang ◽  
Yanbing Hou ◽  
...  

Abstract Background Mitochondrial dysfunction is involved in the pathogenicity of Parkinson’s disease (PD). However, the genetic roles of mitochondrial function-associated genes responsible for PD need to be replicated in different cohorts. Methods Whole-exome and Sanger sequencing were used to identify the genetic etiology of 400 autosomal dominant-inherited PD (ADPD) patients. Variants in six dominant inherited mitochondrial function-associated genes, including HTRA2, CHCHD2, CHCHD10, TRAP1, HSPA9 and RHOT1, were analyzed. Results A total of 12 rare variants identified in the five genes accounted for 3% of ADPD cases, including 0.5% in HTRA2, 0.8% in CHCHD2, 1% in TRAP1, 0.3% in RHOT1 and 0.5% in HSPA9. Among them, five novel variants, p.E4A, p.R13Cfs*107 and p.R449X in TRAP1, p.S95N in RHOT1 and p.N180I in HSPA9, were identified in ADPD patients. Evidence of a founder event that occurred exclusively in Asia was identified in two probands with p.P53Afs*37 in CHCHD2, which was further observed in one patient from 300 sporadic cases. Based on burden analysis, CHCHD2 tended to be slightly enriched in ADPD. Clinically, all patients carrying mutations in the genes presented typical motor symptoms and a good response to L-DOPA. Most of them had slower disease progression (8/12) and mild cognitive impairment (9/12), but the age of onset varied. No rare variant was detected in CHCHD10. Conclusion Our study expands the mutation spectra and enhances the understanding of the clinical phenotype of PD patients with mitochondrial function-related gene variants. Additionally, the CHCHD2 gene should be given more attention in PD originating in the Chinese population.


2020 ◽  
Author(s):  
Li Jiang ◽  
Jun-pu Mei ◽  
Yu-wen Zhao ◽  
Rui Zhang ◽  
Hong-xu Pan ◽  
...  

Abstract Background NUS1 has recently been identified as a candidate risk gene for Parkinson’s disease (PD), but the contribution of NUS1 rare and low-frequency variants to PD susceptibility and phenotypes is largely unknown. Methods In our case-control study, whole-exome or Sanger sequencing was performed on the subjects (4,779 cases vs. 4,442 controls) to analyze the coding sequence of NUS1 . The associations between variants and phenotypic data were analyzed using sequence kernel association test and regression models. Results A total of 13 variants were identified. Ten of them in 12 patients and one control were rare variants and three were low-frequency variants. Three rare variants (R86L, N144K, D163H) might be pathogenic. We identified a significant burden of rare NUS1 variants in PD (adjusted P=0.016). Two low-frequency variants, rs550854234 and rs539668656, were associated with PD (odds ratio = 0.76, adjusted P = 0.041; odds ratio = 2.80, adjusted P = 0.016; respectively). Analyses stratified by age at onset showed that the same two variants were associated with late-onset PD (odds ratio = 0.66, adjusted P = 0.025; odds ratio = 2.96, adjusted P = 0.025; respectively). The genotype-phenotype associations of these variants showed that patients with PD carrying rare variants, rs550854234 or rs539668656 were significantly associated with earlier onset age, emotional impairment and tremor severity. Conclusions Our study suggests that rare and low-frequency NUS1 variants play an important role in the pathogenesis and phenotype of PD. Moreover, our data will help understand the role of NUS1 plays in the pathogenesis of PD and further the development of personalized treatments for PD.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
A. Planas-Ballvé ◽  
D. Vilas

Cognitive impairment is common in idiopathic Parkinson’s disease (PD). Knowledge of the contribution of genetics to cognition in PD is increasing in the last decades. Monogenic forms of genetic PD show distinct cognitive profiles and rate of cognitive decline progression. Cognitive impairment is higher in GBA- and SNCA-associated PD, lower in Parkin- and PINK1-PD, and possibly milder in LRRK2-PD. In this review, we summarize data regarding cognitive function on clinical studies, neuroimaging, and biological markers of cognitive decline in autosomal dominant PD linked to mutations in LRRK2 and SNCA, autosomal recessive PD linked to Parkin and PINK1, and also PD linked to GBA mutations.


2020 ◽  
Author(s):  
Yuri L. Sosero ◽  
Sara Bandres-Ciga ◽  
Ziv Gan-Or ◽  
Lynne Krohn

AbstractThree family studies identified three different variants in the peptidyl-tRNA hydrolase domain containing 1 gene (PTRHD1) in patients affected by syndromic parkinsonism. In the current study, our objective was to investigate whether PTRHD1 variants are associated with Parkinson’s disease (PD) risk and age at onset (AAO). To evaluate the association between PTRHD1 and PD risk, we analyzed whole genome sequencing (WGS) data of 1,647 PD cases and 1,050 healthy controls, as well as genome-wide imputed genotyping data on 14,671 PD cases and 17,667 controls, all of European ancestry. Furthermore, we examined the association of PTRHD1 with PD risk and AAO using summary statistics data from the most recent PD genome-wide association study (GWAS) meta-analyses. Our results show no association between PTRHD1 and PD risk or AAO. We conclude that PTRHD1 does not play a major role in PD in the European population. Further large-scale studies including subjects with different ancestry and family trios might further clarify the relationship of this gene with PD and atypical parkinsonism.


The Lancet ◽  
2005 ◽  
Vol 365 (9457) ◽  
pp. 412-415 ◽  
Author(s):  
A DIFONZO ◽  
C ROHE ◽  
J FERREIRA ◽  
H CHIEN ◽  
L VACCA ◽  
...  

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