Article

Mutations in the Parkinson's disease genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA), are not associated with essential tremor

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, NY, NY 10032, USA.
Parkinsonism & Related Disorders (Impact Factor: 4.13). 07/2009; 16(2):132-5. DOI: 10.1016/j.parkreldis.2009.05.008
Source: PubMed

ABSTRACT We evaluated an association between essential tremor (ET) and the Parkinson's disease (PD) genes, Leucine Rich Repeat Kinase 2 (LRRK2) and Glucocerebrosidase (GBA). Clinical studies demonstrate an association between ET and PD, suggesting possible shared pathophysiologies, yet LRRK2 has rarely been studied in ET, and GBA, not at all. ET cases (n = 275, including 42 with rest tremor) and controls (n = 289) were enrolled in an epidemiological study (Columbia University). Post-mortem brain tissue samples were obtained on 24 additional ET cases, including 3 with brainstem Lewy bodies. We performed a comprehensive analysis of the LRRK2 gene by genotyping 4 LRRK2 mutations (G2019S, I2020T, R1441C and Y1699C), 2 rare LRRK2 variants (L1114L and I1122V) and 19 LRRK2 SNPs. All GBA exons were sequenced in a subset of 93 Ashkenazi Jewish (AJ) cases, 62 AJ controls and 24 ET brains. LRRK2 mutations were not found in any ET cases or ET brains and none of the LRRK2 SNPs was associated with ET. GBA mutations were found in 7.5% (7/93) of AJ ET cases and 4.8% (3/62) of AJ controls (p = 0.75). 8.3% (2/24) of ET brains carried a GBA mutation. Four different heterozygous mutations were identified, including 3 previously reported mutations (N370S, R496H, and E326K) and 1 new missense variant (R44C). As suggested by several smaller prior reports, the known mutations for the LRRK2 gene are not risk factors for ET. Furthermore, a similar frequency of GBA mutations in AJ ET cases and controls suggests that GBA is not a common cause of ET either.

0 Followers
 · 
111 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent reports of death and illness caused by adverse drug reactions have boosted rational drug design research. It has been shown through sequencing of the entire human genome that human genetic variations play a key role in adverse reactions to drugs as well as in differences in the effectiveness of drug treatments. The advent of high-throughput DNA sequencing technologies with bioinformatics of system biology have allowed the easy identification of genetic variations and all other pharmacogenetic variants in a single assay, thus permitting truly personalized drug treatment. This would be particularly valuable for many patients with chronic diseases who must take many medications concurrently. In this review, we have focused on pharmacogenomics for the prediction of variable drug responses between individuals with relevant genetic variations through new DNA sequencing technologies and provided directions for personalized drug therapy in the future.
    Genes & genomics 12/2011; 33(6). DOI:10.1007/s13258-011-0124-z · 0.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetics research is an avenue towards understanding essential tremor (ET). Advances have been made in genetic linkage and association: there are three reported ET susceptibility loci, and mixed but growing data on risk associations. However, causal mutations have not been forthcoming. This disappointing lack of progress has opened productive discussions on challenges in ET and specifically ET genetics research, including fundamental assumptions in the field. This article reviews the ET genetics literature, results to date, the open questions in ET genetics and the current challenges in addressing them. SEVERAL INHERENT ET FEATURES COMPLICATE GENETIC LINKAGE AND ASSOCIATION STUDIES: high potential phenocopy rates, inaccurate tremor self-reporting, and ET misdiagnoses are examples. Increasing use of direct examination data for subjects, family members, and controls is one current response. Smaller moves towards expanding ET phenotype research concepts into non-tremor features, clinically disputed ET subsets, and testing phenotype features instead of clinical diagnosis against genetic data are gradually occurring. The field has already moved to considering complex trait mechanisms requiring detection of combinations of rare genetic variants. Hypotheses may move further to consider novel mechanisms of inheritance, such as epigenetics. It is an exciting time in ET genetics as investigators start moving past assumptions underlying both phenotype and genetics experimental contributions, overcoming challenges to collaboration, and engaging the ET community. Multicenter collaborative efforts comprising rich longitudinal prospective phenotype data and neuropathologic analysis combined with the latest in genetics experimental design and technology will be the next wave in the field.
    01/2013; 3.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case-control association studies, and exome sequencing in familial ET.
    Acta Neurologica Scandinavica 05/2013; DOI:10.1111/ane.12148 · 2.44 Impact Factor

Full-text (2 Sources)

Download
36 Downloads
Available from
May 22, 2014