Systematically analyzing rare variants of autosomal-dominant genes for sporadic Parkinson's disease in a Chinese cohort

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.

Download Full-text

Rare Variants Analysis of Lysosomal Related Genes in Early-Onset and Familial Parkinson’s Disease in a Chinese Cohort

Journal of Parkinson s Disease ◽

10.3233/jpd-212658 ◽

2021 ◽

pp. 1-11

Author(s):

Yong-Ping Chen ◽

Xiao-Jing Gu ◽

Wei Song ◽

Yan-Bing Hou ◽

Ru-Wei Ou ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Onset ◽

Rare Variants ◽

Lysosomal Storage ◽

Asian Populations ◽

Whole Exome ◽

Gene Level ◽

Chinese Cohort

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

Download Full-text

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

10.21203/rs.3.rs-23120/v1 ◽

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.

Download Full-text

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

US Neurology ◽

10.17925/usn.2009.05.01.34 ◽

2009 ◽

Vol 05 (01) ◽

pp. 34 ◽

Cited By ~ 1

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.

Download Full-text

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

European Neurological Review ◽

10.17925/enr.2009.04.01.40 ◽

2009 ◽

Vol 4 (1) ◽

pp. 40 ◽

Cited By ~ 1

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.

Download Full-text

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

The Lancet ◽

10.1016/s0140-6736(05)70236-1 ◽

2005 ◽

Vol 365 (9457) ◽

pp. 412-415 ◽

Cited By ~ 8

Author(s):

A DIFONZO ◽

C ROHE ◽

J FERREIRA ◽

H CHIEN ◽

L VACCA ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Gene Mutation ◽

Autosomal Dominant

Download Full-text

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

Genes ◽

10.3390/genes12030430 ◽

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.

Download Full-text

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

npj Genomic Medicine ◽

10.1038/s41525-020-00163-8 ◽

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.

Download Full-text

Common and rare variants in HFE are not associated with Parkinson's disease in Europeans

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.05.019 ◽

2021 ◽

Author(s):

Prabhjyot Saini ◽

Sara Bandres-Ciga ◽

Jose Luis Alcantud ◽

Clara Ruz ◽

Ronald B. Postuma ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rare Variants

Download Full-text