References of "Klein, Christine"
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See detailLIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort
Usnich, Tatiana; Vollstedt, Eva-Juliane; Schell, Nathalie et al

in Frontiers in Neurology (2021), 12

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 ( LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2 -linked PD is clinically indistinguishable ... [more ▼]

Background: Pathogenic variants in the Leucine-rich repeat kinase 2 ( LRRK2) gene are the most common known monogenic cause of Parkinson's disease (PD). LRRK2 -linked PD is clinically indistinguishable from idiopathic PD and inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity that differ across ethnicities and geographic regions. Objective: To systematically assess clinical signs and symptoms including non-motor features, comorbidities, medication and environmental factors in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls. A further focus is to enable the investigation of modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data. Methods: Eligible participants are invited for a personal or online examination which comprises completion of a detailed eCRF and collection of blood samples (to obtain DNA, RNA, serum/plasma, immune cells), urine as well as household dust. We plan to enroll 1,000 participants internationally: 300 with LRRK2 -linked PD, 200 with LRRK2 pathogenic variants but without PD, 100 PD patients with pathogenic variants in the GBA or PRKN genes, 200 patients with idiopathic PD, and 200 healthy persons without pathogenic variants. Results: The eCRF consists of an investigator-rated (1 h) and a self-rated (1.5 h) part. The first part includes the Movement Disorder Society Unified Parkinson's Disease Rating, Hoehn \&Yahr, and Schwab \& England Scales, the Brief Smell Identification Test, and Montreal Cognitive Assessment. The self-rating part consists of a PD risk factor, food frequency, autonomic dysfunction, and quality of life questionnaires, the Pittsburgh Sleep Quality Inventory, and the Epworth Sleepiness as well as the Hospital Anxiety and Depression Scales. The first 15 centers have been initiated and the first 150 participants enrolled (as of March 25th, 2021). Conclusions: LIPAD is a large-scale international scientific effort focusing on deep phenotyping of LRRK2 -linked PD and healthy pathogenic variant carriers, including the comparison with additional relatively frequent genetic forms of PD, with a future perspective to identify genetic and environmental modifiers of penetrance and expressivity Clinical Trial Registration: ClinicalTrials.gov , NCT04214509. [less ▲]

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See detailDiscordant Monozygotic Parkinson Disease Twins: Role of Mitochondrial Integrity
Dulovic-Mahlow, Marija; König, Inke R.; Trinh, Joanne et al

in Annals of Neurology (2020)

Objective Even though genetic predisposition has proven to be an important element in Parkinson's disease (PD) etiology, monozygotic (MZ) twins with PD displayed a concordance rate of only about 20 ... [more ▼]

Objective Even though genetic predisposition has proven to be an important element in Parkinson's disease (PD) etiology, monozygotic (MZ) twins with PD displayed a concordance rate of only about 20% despite their shared identical genetic background. Methods We recruited 5 pairs of MZ twins discordant for idiopathic PD and established skin fibroblast cultures to investigate mitochondrial phenotypes in these cellular models against the background of a presumably identical genome. To test for genetic differences, we performed whole genome sequencing, deep mitochondrial DNA (mtDNA) sequencing, and tested for mitochondrial deletions by multiplex real‐time polymerase chain reaction (PCR) in the fibroblast cultures. Further, the fibroblast cultures were tested for mitochondrial integrity by immunocytochemistry, immunoblotting, flow cytometry, and real‐time PCR to quantify gene expression. Results Genome sequencing did not identify any genetic difference. We found decreased mitochondrial functionality with reduced cellular adenosine triphosphate (ATP) levels, altered mitochondrial morphology, elevated protein levels of superoxide dismutase 2 (SOD2), and increased levels of peroxisome proliferator‐activated receptor‐gamma coactivator‐α (PPARGC1A) messenger RNA (mRNA) in skin fibroblast cultures from the affected compared to the unaffected twins. Further, there was a tendency for a higher number of somatic mtDNA variants among the affected twins. Interpretation We demonstrate disease‐related differences in mitochondrial integrity in the genetically identical twins. Of note, the clinical expression matches functional alterations of the mitochondria [less ▲]

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See detailMitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism
Borsche, Max; Koenig, Inke; Delcambre, Sylvie UL et al

in Brain: a Journal of Neurology (2020)

There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the ... [more ▼]

There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients. [less ▲]

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See detailAge at Onset of LRRK2 p.Gly2019Ser Is Related to Environmental and Lifestyle Factors
Lüth, Theresa; König, Inke R; Grünewald, Anne UL et al

in Movement Disorders (2020), 35(10), 1854-1858

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See detailMitochondria and Parkinson's Disease: Clinical, Molecular, and Translational Aspects
Borsche, Max; Pereira, Sandro; Klein, Christine et al

in Journal of Parkinson's Disease (2020)

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See detailMitochondrial Mechanisms of LRRK2 G2019S Penetrance
Delcambre, Sylvie UL; Ghelfi, Jenny UL; Ouzren, Nassima et al

in Frontiers in Neurology (2020)

Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson’s disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is ... [more ▼]

Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson’s disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is regulated by autophosphorylation. Yet, the penetrance of this gain-of-function mutation is incomplete, and thus far, few factors have been correlated with disease status in carriers. This includes (i) LRRK2 autophosphorylation in urinary exosomes, (ii) serum levels of the antioxidant urate, and (iii) abundance of mitochondrial DNA (mtDNA) transcription-associated 7S DNA. In light of a mechanistic link between LRRK2 kinase activity and mtDNA lesion formation, we previously investigated mtDNA integrity in fibroblasts from manifesting (LRRK2+/PD+) and non-manifesting carriers (LRRK2+/PD−) of the G2019S mutation as well as from aged-matched controls. In our published study, mtDNA major arc deletions correlated with PD status, with manifesting carriers presenting the highest levels. In keeping with these findings, we now further explored mitochondrial features in fibroblasts derived from LRRK2+/PD+ (n = 10), LRRK2+/PD− (n = 21), and control (n = 10) individuals. In agreement with an accumulation of mtDNA major arc deletions, we also detected reduced NADH dehydrogenase activity in the LRRK2+/PD+ group. Moreover, in affected G2019S carriers, we observed elevated mitochondrial mass and mtDNA copy numbers as well as increased expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates antioxidant signaling. Taken together, these results implicate mtDNA dyshomeostasis—possibly as a consequence of impaired mitophagy—in the penetrance of LRRK2-associated PD. Our findings are a step forward in the pursuit of unveiling markers that will allow monitoring of disease progression of LRRK2 mutation carriers [less ▲]

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See detailA patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.
Boussaad, Ibrahim UL; Obermaier, Carolin D.; Hanss, Zoé et al

in Science translational medicine (2020), 12(560),

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic ... [more ▼]

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. [less ▲]

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See detailMtDNA deletions discriminate affected from unaffected LRRK2 mutation carriers
Ouzren, Nassima UL; Delcambre, Sylvie UL; Ghelfi, Jenny UL et al

in Annals of Neurology (2019), 86(2), 324-326

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See detailUsing global team science to identify genetic parkinson's disease worldwide
Krüger, Rejko UL; Vollstedt, Eva‐Juliane; Kasten, Meike et al

in Annals of Neurology (2019)

Large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.

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See detailImpaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients
Nickels, Sarah UL; Walter, Jonas; Bolognin, Silvia UL et al

in Parkinsonism and Related Disorders (2019)

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See detailGenotype-phenotype relations for the Parkinson’s disease genes SNCA, LRRK2, VPS35: MDSGene Review.
Trinh, Joanne; Zeldenrust, Florentine M. J.; Huang, Jana et al

in Movement Disorders (2018), 33(12), 1857-1870

This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total ... [more ▼]

This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P < 0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l-dopa. [less ▲]

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See detailFDG-PET and metabolomics in PD-associated GBA variants
Greuel, Andrea; Trezzi, Jean-Pierre; Glaab, Enrico UL et al

in Movement Disorders (2018), 33(2), 599

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See detailFaithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia
Grütz, Karen; Weisbach, Anne; Lohmann, Katja et al

in Scientific Reports (2017)

In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been ... [more ▼]

In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ε-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ε-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease. [less ▲]

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See detailEIF4G1 is neither a strong nor a common risk factor for Parkinson's disease: evidence from large European cohorts
Huttenlocher, Johanna; Krüger, Rejko UL; Capetian, Philipp et al

in Journal of medical genetics (2014), 0

BACKGROUND: Missense mutations in the eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with ... [more ▼]

BACKGROUND: Missense mutations in the eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene have previously been implicated in familial Parkinson's disease (PD). A large PD family with autosomal-dominant segregation showed a heterozygous missense mutation and additional patients were found to have unique sequence variants that have not been observed in controls. Subsequent studies have reported contradictory findings. METHODS: We assessed the relevance of EIF4G1 mutations in a European cohort of 2146 PD patients. Of these, 2051 sporadic PD patients were screened for the reported p.Ala502Val and p.Arg1205His mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal-dominant inheritance. Moreover, we imputed the p.Arg1205His substitution and tested for association with PD in the Icelandic population (93 698 samples). RESULTS: We did not observe the presence of the p.Ala502Val substitution in our cohort; however, the p.Arg1205His mutation was identified in one sporadic PD patient. The same mutation was also found in 76 Icelandic subjects older than 65 years using haplotype imputing. Only five of these subjects reported PD symptoms (OR 1.3, p=0.50). Thus, if causal, the p.Arg1205His EIF4G1 mutation has a low penetrance or a late onset manifestation. A novel variant p.Arg566Cys found in a patient with familial PD did not cosegregate with PD in all three affected siblings. All further recently published EIF4G1 mutations found in our cohort are likely to be benign polymorphisms. CONCLUSIONS: This is the largest genetic study of EIF4G1 mutations in PD. Our data do not support the EIF4G1 gene as a high-risk PD locus, neither for the familial nor the sporadic condition. Furthermore, the p.Arg1205His mutation is not significantly associated with increased risk of PD in the Icelandic population. Therefore, caution should be exercised when interpreting EIF4G1 genotyping results in isolated patients and PD families. In summary, diagnostic testing of EIF4G1 should not be recommended in clinical settings. [less ▲]

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See detailGlobal investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease.
Theuns, Jessie; Verstraeten, Aline; Sleegers, Kristel et al

in Neurology (2014)

OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO ... [more ▼]

OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort. METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease. [less ▲]

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See detailProtective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.
Heckman, Michael G.; Elbaz, Alexis; Soto-Ortolaza, Alexandra I. et al

in Neurobiology of aging (2014), 35(1), 2665-14

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H ... [more ▼]

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p >/= 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. [less ▲]

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See detailPopulation-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.
Heckman, Michael G.; Soto-Ortolaza, Alexandra I.; Aasly, Jan O. et al

in Movement disorders : official journal of the Movement Disorder Society (2013), 28(12), 1740-4

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease ... [more ▼]

BACKGROUND: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. METHODS: The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. RESULTS: Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. CONCLUSIONS: Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. [less ▲]

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See detailRole of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.
Sharma, Manu; Maraganore, Demetrius M.; Ioannidis, John P. A. et al

in Neurobiology of aging (2011), 32(11), 21081-5

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for ... [more ▼]

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. [less ▲]

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