Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia

doi:10.1016/j.parkreldis.2007.11.016

Parkinsonism & Related Disorders

Volume 15, Issue 2, February 2009, Pages 105-109

https://doi.org/10.1016/j.parkreldis.2007.11.016 Get rights and content

Abstract

A family history of Parkinson's disease (PD) is the most commonly reported risk factor after age, suggesting a genetic component to the disease in a sub-group of patients. Mutations in at least six genes have been identified that can lead to monogenic forms of PD. We screened a sample of 74 early-onset PD cases out of a cohort of 950 patients (onset <50 years) for genetic abnormalities in known familial Parkinsonism genes. A self-reported family history of PD existed for 30 patients (40.5%). Of these, 13 each had a first- or a second-degree relative with PD and four reported a more distant relative with PD.

The entire coding region of the PRKN (MIM 602544), DJ-1 (MIM 602533) and PINK1 (MIM 698309) genes, and exon 41 of the LRRK2 gene (MIM 609007) were screened by direct sequencing. All exons of PRKN were examined for gene-dosage abnormalities.

Screening identified five patients with putative genetic disease: two patients carried PRKN mutations (p.G12R heterozygous and p.G430D homozygous), one patient carried a p.G411S heterozygous amino acid change in the PINK1 gene and two individuals were heterozygous for the common p.G2019S mutation in LRRK2. No alpha-synuclein or DJ-1 variants were observed.

Our data suggest that approximately 7% of early-onset PD cases seen in Queensland movement disorders clinics have mutations involving known PARK genes.

Introduction

Parkinson's disease (PD) is a neurodegenerative condition with a typical onset in the seventh decade, however, about 4% of PD patients present with early-onset before the age of 50 years [1]. It is a complex, multifactorial disorder, comprising genetic and environmental components. The majority of cases appear to be sporadic or idiopathic, however, in the recent past a number of mutations in at least six genes (PARK1, 2, 5, 6, 7, and 8) have been identified as being causative in the familial form of the condition, accounting for a small number of all PD cases. Mutations in these genes may lead to the disease phenotype and are often characterized by an earlier onset (under the age of 50 years) with or without Lewy body pathology. It is to be expected that more mutations causative for the disease in ‘sporadic’ PD will be identified in the future, adding to the number of distinct genetic forms of PD. The aetiology of the sporadic form of PD is still unclear but identification of molecular mechanisms and gene products underlying the disease in its monogenic form have shed some light on possible pathways involved in the non-hereditary form of the condition.

As an early disease onset is frequent in familial PD, we undertook in this study to estimate the prevalence of known genetic forms of Parkinsonism in a typical Australian population (Queensland) by screening a subset of early-onset cases, derived from a large movement disorders clinic in Brisbane, Australia.

Section snippets

Sampling frame

Patients were derived from a case series of 950 patients with a diagnosis of PD seen in one specialist movement disorders practice in Brisbane, between 2000 and 2005. Informed consent was obtained from all participating patients.

Patient selection

Patients were included in the study if they (1) received a diagnosis of probable PD according to stringent clinical and neurological criteria; (2) exhibited onset of symptoms ≤50 years; and (3) had been seen at the clinic between 2001 and 2005.

Patient ethnicity

Patients in this sample

Results

Seventy-four patients met the inclusion criteria. Demographic data are shown in Table 2. In this sample, males were slightly over-represented (n = 44, 59.5%). A self-reported family history of PD existed for 30 patients (40.5%). Of these, 13 each had a first- or a second-degree relative with PD and four patients reported a more distant relative affected by the condition. Among the first-degree relatives, there were six affected fathers and four affected mothers. More specific unambiguous

Discussion

The importance of genetic factors for the aetiology of PD has been debated controversially for a long time. Longitudinal twin studies argued for a genetic element contributing to the condition whereas other cross-sectional studies could find no evidence for inheritance [4], [5]. In the meantime, at least five genes have been identified that are implicated in the development of a monogenic form of PD (PARK1, 2, 6, 7, and 8). These monogenic forms of the condition may mimic clinically sporadic PD

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Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants
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α-synuclein (αS) is the key component of synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. αS was first linked to PD through the identification of point mutations in the SNCA gene, causing single amino acid substitutions within αS and familial autosomal dominant forms of PD that profoundly accelerated disease onset by up to several decades. At least eight single-point mutations linked to familial PD (A30G/P, E46K, H50Q, G51D, and A53T/E/V) are located in proximity of the region preceding the non-β amyloid component (preNAC) region, strongly implicating its pathogenic role in αS-mediated cytotoxicity. Furthermore, lipids are known to be important for native αS function, where they play a key role in the regulation of synaptic vesicle docking to presynaptic membranes and dopamine transmission. However, the role of lipids in the function of mutant αS is unclear. Here, we studied αS aggregation properties of WT αS and five of the most predominant single-point missense mutants associated with early onset PD in the presence of anionic 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine lipid vesicles. Our results highlight significant differences between aggregation rates, the number of aggregates produced, and overall fibril morphologies of WT αS and the A30P, E46K, H50Q, G51D, and A53T missense mutants in the presence of lipid vesicles. These findings have important implications regarding the interplay between the lipids required for αS function and the individual point mutations known to accelerate PD and related diseases.
Prevalence of ten LRRK2 variants in Parkinson's disease: A comprehensive review
2022, Parkinsonism and Related Disorders
Variants in the leucine-rich repeat kinase 2 gene (LRRK2) are risk factors for Parkinson's disease (PD), but their prevalence varies geographically, reflecting the locations of founder events and dispersion of founders' descendants.
A comprehensive literature review was conducted to identify studies providing prevalence estimates for any of ten variants in LRRK2 (G2019S, R1441C, R1441G, R1441H, I2020T, N1437H, Y1699C, S1761R, G2385R, R1628P) among individuals with PD globally. We calculated crude country-specific variant prevalence estimates and, when possible, adjusted estimates for ethno-racial composition. For clinic-based studies, probands were used over other familial cases, whereas for population-based studies, all PD cases were used.
The analysis included 161 articles from 52 countries yielding 581 prevalence estimates across the ten variants. G2019S was the most common variant, exceeding 1.0% in 26 of 51 countries with estimates. The other variants were far less common. G2385R and R1628P were observed almost exclusively in East Asian countries, where they were found in ∼5–10% of cases. All prevalence estimates adjusted for ethno-racial composition were lower than their unadjusted counterparts, although data permitting this adjustment was only available for six countries.
Except for G2019S, the LRRK2 variants covered in this review were uncommon in most countries studied. However, there were countries with higher prevalence for some variants, reflecting the uneven geographic distribution of LRRK2 variants. The fact that ethno-racial group‒adjusted estimates were lower than crude estimates suggests that estimates derived largely from clinic-based studies may overstate the true prevalence of some LRRK2 variants in PD.
Comprehensive assessment of PINK1 variants in Parkinson's disease
2020, Neurobiology of Aging
Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early-onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here, we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large data sets totalling 376,558 individuals including 13,708 cases with Parkinson's disease and 362,850 control subjects. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a robust risk factor for Parkinson's disease.
Genetic variants of PARK genes in Korean patients with early-onset Parkinson's disease
2019, Neurobiology of Aging
Citation Excerpt :
Therefore, based on our results, the number of PARK genes investigated can affect the detection rate, although the rate for genetic PD was still low. Interestingly, the detection rate for pathogenic PARK gene variants differed among the previous studies (Choi et al., 2008; Erer et al., 2016; Macedo et al., 2009; Mellick et al., 2009), and no patients with EOPD had PRKN variants in our study. Regional and ethnic differences may account for this discrepancy.
Early-onset Parkinson's disease (EOPD) can be linked to different genetic backgrounds depending on the disease characteristics. In Korean patients with EOPD, however, only 5 PARK genes have been tested. We recruited 70 patients with EOPD from 4 hospitals in Korea, and 12 PARK genes were screened via multigene panel sequencing. Large insertions or deletions were confirmed by multiplex ligation-dependent probe amplification. We found 20 rare variants (2 in SNCA, 2 in PRKN, 6 in LRRK2, 3 in PINK1, 1 in DJ1, 4 in FBX07, 1 in HTRA2, and 1 in EIG4G1) in 20 subjects regardless of heterogeneity. Two pathogenic variants (SNCA in 2 subjects and DJ1 in one) were from 3 subjects, and 7 likely pathogenic variants (SNCA, LRRK2, FBXO7, and 2 in PINK1 and PRKN) from 7. Akinetic-rigid subtype and dystonia were more common in patients with EOPD with rare variants than in those without rare variants. Multigene panel tests can be effective at identifying genetic variants in patients with EOPD. In addition, we suggest there are different genetic backgrounds in patients with EOPD.
Pipeline to gene discovery - Analysing familial Parkinsonism in the Queensland Parkinson's Project
2018, Parkinsonism and Related Disorders
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Interestingly, the 40bp deletion in PARK2 has been seen to segregate with disease in a dominant inheritance pattern, albeit with reduced penetrance, in a family with atypical Parkinsonism [29]. Aside from the previously identified p.G411S mutation in PINK1 in the proband of family #019 [15], we did not identify any additional rare mutations in PINK1 in the proband through WES. Recently, this variant was shown to increase the risk of PD by 2.9 times through a dominant-negative mechanism [30]; however, the variant itself does not segregate with disease in this family.
Family based study designs provide an informative resource to identify disease-causing mutations. The Queensland Parkinson's Project (QPP) has been involved in numerous genetic screening studies; however, details of the families enrolled into the register have not been comprehensively reported. This article characterises the families enrolled in the QPP and summarises monogenic forms of hereditary Parkinsonism found in the register.
The presence of pathogenic point mutations and copy number variations (CNVs) were, generally, screened in a sample of over 1000 PD patients from the total of 1725. Whole exome sequencing (WES) was performed on eighteen probands from multiplex families.
The QPP contains seventeen incidences of confirmed monogenic forms of PD, including LRRK2 p.G2019S, VPS35 p.D620N, SNCA duplications and PARK2 p.G430D (hom) & exon 4 deletion (hom). Of these seventeen, five belong to multi-incident families, while another eight have a family history of at least one other case of PD. In additional families, WES did not identify known forms of monogenic Parkinsonism; however, three heterozygous mutations in PARK2, p.R275W, p.Q34fs, and a 40bp deletion in exon 3 were identified. Of these three mutations, only the 40bp deletion segregated with disease in a dominant inheritance pattern.
Eighteen probands have screened negative for known CNVs and mutations that cause clear monogenic forms of PD. Each family is a candidate for further genetic analysis to identify genetic variants segregating with disease. The families enrolled in the QPP provide a useful resource to aid in identifying novel forms of monogenic PD.
Nonmotor Signs in Genetic Forms of Parkinson's Disease
2017, International Review of Neurobiology
Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, “idiopathic” PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment. Notably, relatively few studies specifically addressed NMS in genetic PD and missing data ranged from 42% to 100%. Diagnostic criteria and examination methods were variable and cases differed widely for age at onset, disease duration, ethnicity, treatment, and comorbidity. Although in comparison to IPD, SNCA duplication carriers have the most similar course of disease, even for duplication carriers the frequencies of dementia, hallucinations, and depression seem higher than in IPD. Supporting the notion that LRRK2-linked PD has a similar course to iPD but is slightly more benign, the frequency of dementia is below that of iPD. For Parkin, the frequency of cognitive decline falls within the range of the general population above the age of 65 years. GBA mutations are associated with a distinct profile of cognitive impairment and a greater prevalence of depression. Despite the current data gaps, NMS should be considered as an important and often treatable concomitant feature of genetic parkinsonism.

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Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia

Abstract

Introduction

Section snippets

Sampling frame

Patient selection

Patient ethnicity

Results

Discussion

J Neurol Sci

Parkinsonism Relat Disord

Lancet

Lancet

Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity

Am J Epidemiol

Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism

Nature

Parkinson disease in twins: an etiologic study

JAMA

The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins

Ann Neurol

Familial juvenile Parkinsonism: clinical and pathologic study in a family

Neurology

Evaluation of 50 probands with early-onset Parkinson's disease for parkin mutations

Neurology

Frequency of parkin mutations in late-onset Parkinson's disease

Ann Neurol

Association between early-onset Parkinson's disease and mutations in the parkin gene

N Engl J Med

Parkin mutations are frequent in patients with isolated early-onset Parkinsonism

Brain

Parkin disease: a phenotypic study of a large case series

Brain

Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study

Arch Neurol