Mutation of the LRRK2 gene has been associated with autosomal dominant parkinsonism. An R1441C pathogenic substitution was identified in Family D, a large Western Nebraskan kindred, with four members ...demonstrating pleomorphic pathology at autopsy. One member of this family displayed tau pathology suggestive of progressive supranuclear palsy (PSP). To evaluate the influence of mutation at the R1441 residue in this disorder we screened a series of 242 pathologically confirmed PSP cases. No evidence was found for the presence of a mutation at this codon in our series. These data would suggest that this Lrrk2 variant does not contribute in susceptibility to PSP.
Background and purpose: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to ...validate previously published findings, evaluating gene–gene interactions between SNCA, MAPT, and GSK3B in association with PD.
Methods: Three Caucasian PD patient–control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2‐discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552.
Results: Our findings indicate that as previously reported, the SNCA rs356219‐G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair‐wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219‐G and MAPT rs1052553‐H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects.
Conclusions: In the Caucasian patient–control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.
Since the first description of Parkinson's disease (PD) in 1817 attempts have been made to resolve the etiology of this common neurodegenerative disorder. In the last century the influence of ...heredity in PD was controversial. The identification of mutations in six genes responsible for Mendelian forms of PD; α‐synuclein (SNCA), parkin (PRKN), ubiquitin C‐terminal hydrolase L1 (UCH‐L1), oncogene DJ‐1, PTEN‐induced putative kinase 1 (PINK1), and most recently leucine‐rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease. The exact relationship of these familial disorders and related genes to the more common sporadic form is currently uncertain. The identification of LRRK2 mutations and the association of common variants in SNCA and UCH‐L1 in apparently sporadic late‐onset disease indicate these genes may be of greater importance than previously believed. The protein products of the six genes are involved in different pathways of neurodegeneration and have opened new avenues of research. This focused research will lead to the development of novel targeted therapies, which may revolutionize the treatment of PD for a substantial proportion of patients.
Pathogenic mutations in the leucine‐rich repeat kinase 2 gene (LRRK2; PARK8) have been implicated in autosomal dominant, late‐onset parkinsonism. The LRRK2 6055G > A (G2019S) mutation is the most ...common reported to date, and has been observed in a number of different European populations. So far, only the LRRK2 4321C > G (R1441G) mutation has been identified in the Spanish population. Herein we have assessed the frequency of G2019S in a referral‐based series of 225 patients with Parkinson's disease (PD) from the region of Asturias, Northern Spain. The mutant allele was identified in five (2.7%) of the sporadic late‐onset patients and was not present in control subjects. All carriers displayed genetic profiles consistent with the same haplotype, as previously reported for Lrrk2 G2019S‐positive subjects. None of these patients presented with a family history of parkinsonism at the time of diagnosis. Thus, approximately 5% of sporadic patients with PD from the North of Spain have either Lrrk2 G2019S or R1441G substitutions.
Over the past two decades, however, the pace of these gains has slowed, especially in several countries in sub-Saharan Africa and south Asia.1-3 Meanwhile, an ever growing body of research shows the ...wider beneficial effect of family planning on improving maternal and child health and survival, increasing economic wellbeing of individuals, families, communities, and nations, fostering environmental sustainability, and empowering women.4-8 The international community and many low-income countries are aiming to accelerate progress in family planning, as made evident by support for FP2020.9 Simultaneously, the world is reflecting on achievements and on gaps remaining in the years since the United Nations Conference on Environment and Development of 1992, the International Conference on Population and Development (ICPD) of 1994, and the Millennium Summit of 2000, which established the Millennium Development Goals (MDGs).
The NIF Rugby High Foot campaign results, with 8 shots to date, are compared with the 2D FCI2 design simulations. A special emphasis is placed on the predictive features and on those areas where some ...work is still required to achieve the best possible modelling of these MJ-class experiments.
Polymorphism of the mtDNA genome has been implicated as playing a role in the development and pathogenesis of Parkinson's disease (PD). A PCR-RFLP methodology was employed to generate genetic ...haplotypes for a cohort of 90 PD sufferers. No association was observed between the various mtDNA haplotypes observed and PD in comparison to healthy aged controls. The longevity-associated European J haplogroup and T haplogroup were identified and were both found to be in tight linkage with the mt4216C polymorphism. The mt4216C variant was observed at a significantly increased frequency in the PD cases (28%) in comparison to the healthy aged controls (15%;
p=0.014). However, when the frequency of the mt4216C variant was examined in a cohort of 200 young controls (18–45 years) a similar frequency to the PD cases (25%) was observed. The frequencies obtained for the two branches of the J haplogroup (J1 and J2) and the T haplogroup in the cohort of PD subjects also reflected those observed for the young controls used in the previous longevity study. These findings lead one to postulate that the mt4216C variant, in linkage with the mtDNA TJ cluster, may influence mitochondrial dysfunction, resulting in an increased risk of PD.
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