scholarly journals Systematic analysis of rare variants in mitochondrial function-associated genes for autosomal-dominant Parkinson’s disease in a Chinese population

2020 ◽  
Author(s):  
Yongping Chen ◽  
Xiaojing Gu ◽  
Ruwei Ou ◽  
Lingyu Zhang ◽  
Yanbing Hou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Function ◽  
Chinese Population ◽  
Autosomal Dominant ◽  
Rare Variants ◽  
Age Of Onset ◽  
Systematic Analysis ◽  
Founder Event ◽  
Mutation Spectra

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.

scholarly journals Whole-exome analysis in Parkinson’s disease reveals a high burden of ultra rare variants in early onset cases

2020 ◽  
Author(s):  
Bernabe I. Bustos ◽  
Dimitri Krainc ◽  
Steven J. Lubbe ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Genetic Component ◽  
Genetic Risk Assessment ◽  
Whole Exome

ABSTRACTParkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. We performed a “hypothesis-free” exome-wide burden-based analysis of different variant frequencies, predicted functional impact and age of onset classes, in order to expand the understanding of rare variants in PD. Analyzing whole-exome data from a total of 1,425 PD cases and 596 controls, we found a significantly increased burden of ultra-rare (URV= private variants absent from gnomAD) protein altering variants (PAV) in early-onset PD cases (EOPD, <40 years old; P=3.95×10−26, beta=0.16, SE=0.02), compared to LOPD cases (>60 years old, late-onset), where more common PAVs (allele frequencies <0.001) showed the highest significance and effect (P=0.026, beta=0.15, SE=0.07). Gene-set burden analysis of URVs in EOPD highlighted significant disease- and tissue-relevant genes, pathways and protein-protein interaction networks that were different to that observed in non-EOPD cases. Heritability estimates revealed that URVs account for 15.9% of the genetic component in EOPD individuals. Our results suggest that URVs play a significant role in EOPD and that distinct etiological bases may exist for EOPD and sporadic PD. By providing new insights into the genetic architecture of PD, our study may inform approaches aimed at novel gene discovery and provide new directions for genetic risk assessment based on disease age of onset.

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

US Neurology ◽  
2009 ◽  
Vol 05 (01) ◽  
pp. 34 ◽  
Author(s):  
Alessandro Ferraris ◽  
Enza Maria Valente ◽  
Anna Rita Bentivoglio ◽  
◽  
◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Clinical Presentation ◽  
Rare Variants ◽  
Age At Onset ◽  
Early Age ◽  
Slow Disease Progression ◽  
Phenotypic Spectrum

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.

scholarly journals A Specific Diplotype H1j/H2 of the MAPT Gene Could Be Responsible for Parkinson’s Disease with Dementia

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Imane Smaili ◽  
Imane Hajjaj ◽  
Rachid Razine ◽  
Houyam Tibar ◽  
Ayyoub Salmi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rare Variants ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Copy Number Variations ◽  
Chromosome 17 ◽  
G2019s Mutation ◽  
Mapt Gene ◽  
Genetic And Environmental Factors

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease. Five to ten percent of patients have monogenic form of the disease, while most of sporadic PD cases are caused by the combination of genetic and environmental factors. Microtubule-associated protein tau (MAPT) has been appointed as one of the most important risk factors for several neurodegenerative diseases including PD. MAPT is characterized by an inversion in chromosome 17 resulting in two distinct haplotypes H1 and H2. Studies described a significant association of MAPT H1j subhaplotype with PD risk, while H2 haplotype was associated with Parkinsonism, particularly to its bradykinetic component. We report here an isolated case displaying an akinetic-rigid form of PD, with age of onset of 41 years and a good response to levodopa, who developed dementia gradually during the seven years of disease progression. The patient does not carry the LRRK2 G2019S mutation, copy number variations, nor pathogenic and rare variants in known genes associated with PD. MAPT subhaplotype genotyping revealed that the patient has the H1j/H2 diplotype, his mother H1j/H1j, his two healthy brothers H1j/H1v and his deceased father was by deduction H1v/H2. The H1j/H2 diplotype was shown in a total of 3 PD patients among 80, who also did not have known PD-causing mutation and in 1 out of 92 healthy individual controls. The three patients with this diplotype all have a similar clinical phenotype. Our results suggest that haplotypes H1j and H2 are strong risk factor alleles, and their combination could be responsible for early onset of PD with dementia.

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 ◽  
◽  
◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Clinical Presentation ◽  
Rare Variants ◽  
Age At Onset ◽  
Slow Disease Progression ◽  
Phenotypic Spectrum ◽  
Phosphatase And Tensin Homologue

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.

Rare variants of LRRK2 for Parkinson’s disease in Chinese population

2017 ◽  
Vol 381 ◽  
pp. 1053
Author(s):  
J. Zhang ◽  
H. Jin ◽  
C. Gu ◽  
C. Mao ◽  
C. Liu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Chinese Population ◽  
Rare Variants

A frequent gene mutation associated with autosomal dominant Parkinson's disease

The Lancet ◽  
2005 ◽  
Vol 365 (9457) ◽  
pp. 412-415 ◽  
Author(s):  
A DIFONZO ◽  
C ROHE ◽  
J FERREIRA ◽  
H CHIEN ◽  
L VACCA ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gene Mutation ◽  
Autosomal Dominant

scholarly journals Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 430
Author(s):  
Steven R. Bentley ◽  
Ilaria Guella ◽  
Holly E. Sherman ◽  
Hannah M. Neuendorf ◽  
Alex M. Sykes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Rare Variants ◽  
Strong Family History ◽  
Disease Mutations ◽  
Whole Exome ◽  
History Of ◽  
Functional Consequences ◽  
Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

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