The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study

Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA.
BMC Medicine (Impact Factor: 7.25). 12/2008; 6(1):32. DOI: 10.1186/1741-7015-6-32
Source: PubMed

ABSTRACT We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.
A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.
Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.
Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

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Available from: Irene Litvan, Sep 26, 2015
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    • "It also appears to be varied between the ethnicities and is higher in Arab Berber than Ashkenazi Jews.71,72 The penetrance reported in initial family-based studies may be overestimated, and the corrected overall penetrance is 67%.73 "
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    ABSTRACT: Discovering genes following Medelian inheritance, such as autosomal dominant-synuclein and leucine-rich repeat kinase 2 gene, or autosomal recessive Parkin, P-TEN-induced putative kinase 1 gene and Daisuke-Junko 1 gene, has provided great insights into the pathogenesis of Parkinson's disease (PD). Genes found to be associated with PD through investigating genetic polymorphisms or via the whole genome association studies suggest that such genes could also contribute to an increased risk of PD in the general population. Some environmental factors have been found to be associated with genetic factors in at-risk patients, further implicating the role of gene-environment interactions in sporadic PD. There may be confusion for clinicians facing rapid progresses of genetic understanding in PD. After a brief review of PD genetics, we will discuss the insight of new genetic discoveries to clinicians, the implications of ethnic differences in PD genetics and the role of genetic testing for general clinicians managing PD patients.
    10/2012; 5(2):33-41. DOI:10.14802/jmd.12009
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    • "Occurrence of LRRK2 mutations in apparently sporadic patients and in healthy control individuals49,56 suggests a reduced penetrance. Estimations of the penetrance for G2019S range from 32% to 74%, depending on the familial background of the families analyzed.49,55,60 G2019S was also found in homozygosity, but with no difference in clinical phenotype compared with heterozygous carriers.57 "
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    ABSTRACT: Parkinson's disease can be caused by rare familial genetic mutations, but in most cases it is likely to result from an interaction between multiple genetic and environmental risk factors. Over recent years, many variants in a growing number of genes involved in the pathogenesis of Parkinson's disease have been identified. Mutations in several genes have been shown to cause familial parkinsonism. In this review, we discuss 12 of them (SNCA, LRRK2, Parkin, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, UCHL1, GIGYF2, HTRA2, and EIF4G1). Additionally, six genes have been shown conclusively to be risk factors for sporadic Parkinson's disease, and are also discussed (GBA, MAPT, BST1, PARK16, GAK, and HLA). Many more genes and genetic loci have been suggested, but need confirmation. There is evidence that pathways involved in the rare familial forms also play a role in the sporadic form, and that the respective genes might also be risk factors for sporadic Parkinson's disease. The identification of genes involved in the development of Parkinson's disease will improve our understanding of the underlying molecular mechanisms, and will hopefully lead to new drug targets and treatment strategies.
    The Application of Clinical Genetics 06/2011; 4(67–80):67-80. DOI:10.2147/TACG.S11639
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    • "As an example, mutations in the LRRK2 gene appear to account for 1-2% of sporadic PD. There also appear to be unknown factors that influence penetrance of LRRK2 mutations that may account for increased prevalence of non-LRRK2 PD phenotypes found in LRRK2 mutation-bearing families (Latourelle, et al., 2008). These potential influences on the PD cellular phenotype would not be expressed in a cybrid model. "
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    ABSTRACT: Sporadic Parkinson's disease (sPD) is a nervous system-wide disease that presents with a bradykinetic movement disorder and frequently progresses to include depression and cognitive impairment. Cybrid models of sPD are based on expression of sPD platelet mitochondrial DNA (mtDNA) in neural cells and demonstrate some similarities to sPD brains. In sPD and CTL cybrids we characterized aspects of mitochondrial biogenesis, mtDNA genomics, composition of the respirasome and the relationships among isolated mitochondrial and intact cell respiration. Cybrid mtDNA levels varied and correlated with expression of PGC-1 alpha, a transcriptional co-activator regulator of mitochondrial biogenesis. Levels of mtDNA heteroplasmic mutations were asymmetrically distributed across the mitochondrial genome; numbers of heteroplasmies were more evenly distributed. Neither levels nor numbers of heteroplasmies distinguished sPD from CTL. sPD cybrid mitochondrial ETC subunit protein levels were not altered. Isolated mitochondrial complex I respiration rates showed limited correlation with whole cell complex I respiration rates in both sPD and CTL cybrids. Intact cell respiration during the normoxic-anoxic transition yielded K(m) values for oxygen that directly related to respiration rates in CTL but not in sPD cell lines. Both sPD and CTL cybrid cells are substantially heterogeneous in mitochondrial genomic and physiologic properties. Our results suggest that mtDNA depletion may occur in sPD neurons and could reflect impairment of mitochondrial biogenesis. Cybrids remain a valuable model for some aspects of sPD but their heterogeneity mitigates against a simple designation of sPD phenotype in this cell model.
    Experimental Neurology 10/2009; 220(2):374-82. DOI:10.1016/j.expneurol.2009.09.025 · 4.70 Impact Factor
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