Topic
LRRK2
About: LRRK2 is a research topic. Over the lifetime, 1791 publications have been published within this topic receiving 104622 citations. The topic is also known as: augmented in rheumatoid arthritis 17 & leucine-rich repeat serine/threonine-protein kinase 2.
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TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
7,387 citations
TL;DR: In this article, the α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of Parkinson's disease, and of glial cell cytoplasmic inclusions.
Abstract: Mutations in the α-synuclein gene ( SNCA ) in the Contursi kindred ([ 1 ][1]) implicated this gene in Parkinson's disease (PD). Subsequently, α-synuclein was identified as the major component of Lewy bodies, the pathological hallmark of PD, and of glial cell cytoplasmic inclusions ([ 2 ][2]).
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3,948 citations
TL;DR: High-resolution recombination mapping and candidate gene sequencing in 46 families found six disease-segregating mutations in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2), which may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
2,757 citations
TL;DR: The cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain is described and this protein is named dardarin, derived from the Basque word dardara, meaning tremor, because of the tremor observed in PD.
2,259 citations
University College London1, Imperial College London2, University of London3, Erasmus University Rotterdam4, French Institute of Health and Medical Research5, Albert Einstein College of Medicine6, Norwegian University of Science and Technology7, University of Washington8, University of Barcelona9, New York State Department of Health10, Monash University11, University of Toronto12, Mayo Clinic13, Mater Misericordiae University Hospital14, UCL Institute of Neurology15, University of Tübingen16
TL;DR: Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD, but this knowledge should be applied with caution in the diagnosis and counselling of patients.
Abstract: Summary Background Mutations in LRRK2 , the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2 -associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2 ? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2 -associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2 -associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.
1,310 citations