Evaluation of
            <i>LRRK2</i>
            G2019S penetrance

Goldwurm, Stefano; Zini, Michela; Mariani, Luigi; Tesei, Silvana; Miceli, Rosalba; Sironi, Francesca; Clementi, Maurizio; Bonifati, Vincenzo; Pezzoli, Gianni

doi:10.1212/01.wnl.0000254483.19854.ef

Cited by 127 publications

(99 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, whether this is ethically appropriate is uncertain, as LRRK2 mutations are not fully penetrant, even by the age of 80 [7,169,170]. Therefore, identification of the very earliest symptoms of LRRK2 patients is likely to be an important step in deciding when to apply therapeutics.…”

Section: Therapeutic Strategies For Lrrk2-associated Pdmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

View full text Add to dashboard Cite

Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

show abstract

Section: Therapeutic Strategies For Lrrk2-associated Pdmentioning

confidence: 99%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

View full text Add to dashboard Cite

show abstract

“…Therefore, to avoid an ascertainment bias, a recent study ascertained LRRK2 mutation carriers through the molecular screening of a large series of consecutive PD patients who were tested regardless of their family history of PD. 75 Testing of the relatives of the PD patients found to have the G2019S mutation yielded much lower estimates of disease penetrance. In this sample, the penetrance by age 50 was 17%, and at age 70 was 54%.…”

Section: Park8: Lrrk2mentioning

confidence: 99%

Genetics of Parkinson disease

Pankratz

Foroud

2007

Genetics in Medicine

110

View full text Add to dashboard Cite

During the past decade five genes have been identified that are important in autosomal dominant and autosomal recessive forms of Parkinson disease. The identification of these genes has increased our understanding of the likely pathogenic mechanisms resulting in disease. However, mutations in these genes likely contribute to disease in fewer than 5% of all cases of Parkinson disease. Thus, researchers have continued to search for genes that may influence disease susceptibility. Molecular diagnostic testing is currently available for four of the genes mutated in Parkinson disease. Evidence for reduced penetrance, possible effects of haploinsufficiency, and the identification of nondisease causing polymorphisms within several of these genes has made genetic counseling challenging.Current recommendations are to limit molecular testing only to those individuals who are symptomatic. Furthermore, because treatment is unaltered by the presence or absence of mutations in these genes, restraint is recommended when considering the value of screening for mutations in a clinical setting. Genet Med 2007:9(12): 801-811.

show abstract

“…In Europe, the frequency of this mutation has been reported to be similar among sporadic (1.9%) [17] and familial (2.9%) [18] cases. Penetrance depends on age, but the reported lifetime prevalence varies from 32% [19] to 85% [20] . The penetrance may be influenced by other factors, including yet undiscovered new genes.…”

Section: Parkinson Diseasementioning

confidence: 99%

Etiology and Pathophysiology of Frontotemporal Dementia, Parkinson Disease and Alzheimer Disease: Lessons from Genetic Studies

Wider

Wszołek²

2008

Neurodegener Dis

View full text Add to dashboard Cite

Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.

show abstract

Evaluation of LRRK2 G2019S penetrance

Cited by 127 publications

References 7 publications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Genetics of Parkinson disease

Etiology and Pathophysiology of Frontotemporal Dementia, Parkinson Disease and Alzheimer Disease: Lessons from Genetic Studies

Contact Info

Product

Resources

About