Maria Jose Marti

Bio: Maria Jose Marti is an academic researcher from Carlos III Health Institute. The author has contributed to research in topics: Ubiquitin ligase & Haplotype. The author has an hindex of 2, co-authored 3 publications receiving 28 citations.

LRRK2 haplotype-sharing analysis in Parkinson's disease reveals a novel p.S1761R mutation.

Abstract: Background and objective. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families. Design. We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations. Results. Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A>C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37–72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease. © 2011 Movement Disorder Society

Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

Abstract: Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

LRRK2: cause, risk, and mechanism.

Abstract: In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last.

Catechol-O-methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease.

Abstract: Background: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability Methods: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations Results: The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 209 [95% confidence interval (CI), 107–406] and 281 [CI, 143–554], respectively) Conclusions: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD © 2011 Movement Disorder Society

Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease.

Abstract: The discovery of LRRK2 mutations as a cause of Parkinson’s disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations. Furthermore, this chapter aims to characterize other definitely/probably pathogenic mutations and risk variants of LRRK2. Finally, we provide some general guidelines for a LRRK2 genetic testing and counseling. In summary, LRRK2 discovery revolutionized the understanding of PD etiology and laid the foundation for a promising future of genetics in PD research.

Analysis of genome-wide association study-linked loci in Parkinson's disease of Mainland China.

Abstract: Background Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) that can modulate the risk of developing Parkinson's disease (PD). Methods We investigated the association of previously identified loci in a Mainland Chinese population to identify a possible ethnic-specific effect with GWAS analysis. Seventeen SNPs were genotyped from those loci using case–control methodology to analyze a total of 1,737 individuals. Results Strong evidence of an association for reference SNP 894278 (rs894278) and rs11931074 on 4q22 throughout the α synuclein (SNCA) region was observed in our study. The SNP rs894278 confers risk via a dominant model and an additive model, whereas the minor allele G of rs11931074 reduces the risk of PD progression. The minor allele frequency of rs11724635 produced weaker signals for PD, but this was not replicated in the genotype after adjusting for age and sex. Conclusions This study yields new clues about GWAS-linked data in patients with PD from Mainland China. © 2013 International Parkinson and Movement Disorder Society