Cargando…
The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study
BACKGROUND: 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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2008
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596771/ https://www.ncbi.nlm.nih.gov/pubmed/18986508 http://dx.doi.org/10.1186/1741-7015-6-32 |
_version_ | 1782161873117904896 |
---|---|
author | Latourelle, Jeanne C Sun, Mei Lew, Mark F Suchowersky, Oksana Klein, Christine Golbe, Lawrence I Mark, Margery H Growdon, John H Wooten, G Frederick Watts, Ray L Guttman, Mark Racette, Brad A Perlmutter, Joel S Ahmed, Anwar Shill, Holly A Singer, Carlos Goldwurm, Stefano Pezzoli, Gianni Zini, Michela Saint-Hilaire, Marie H Hendricks, Audrey E Williamson, Sally Nagle, Michael W Wilk, Jemma B Massood, Tiffany Huskey, Karen W Laramie, Jason M DeStefano, Anita L Baker, Kenneth B Itin, Ilia Litvan, Irene Nicholson, Garth Corbett, Alastair Nance, Martha Drasby, Edward Isaacson, Stuart Burn, David J Chinnery, Patrick F Pramstaller, Peter P Al-hinti, Jomana Moller, Anette T Ostergaard, Karen Sherman, Scott J Roxburgh, Richard Snow, Barry Slevin, John T Cambi, Franca Gusella, James F Myers, Richard H |
author_facet | Latourelle, Jeanne C Sun, Mei Lew, Mark F Suchowersky, Oksana Klein, Christine Golbe, Lawrence I Mark, Margery H Growdon, John H Wooten, G Frederick Watts, Ray L Guttman, Mark Racette, Brad A Perlmutter, Joel S Ahmed, Anwar Shill, Holly A Singer, Carlos Goldwurm, Stefano Pezzoli, Gianni Zini, Michela Saint-Hilaire, Marie H Hendricks, Audrey E Williamson, Sally Nagle, Michael W Wilk, Jemma B Massood, Tiffany Huskey, Karen W Laramie, Jason M DeStefano, Anita L Baker, Kenneth B Itin, Ilia Litvan, Irene Nicholson, Garth Corbett, Alastair Nance, Martha Drasby, Edward Isaacson, Stuart Burn, David J Chinnery, Patrick F Pramstaller, Peter P Al-hinti, Jomana Moller, Anette T Ostergaard, Karen Sherman, Scott J Roxburgh, Richard Snow, Barry Slevin, John T Cambi, Franca Gusella, James F Myers, Richard H |
author_sort | Latourelle, Jeanne C |
collection | PubMed |
description | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. |
format | Text |
id | pubmed-2596771 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-25967712008-12-06 The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study Latourelle, Jeanne C Sun, Mei Lew, Mark F Suchowersky, Oksana Klein, Christine Golbe, Lawrence I Mark, Margery H Growdon, John H Wooten, G Frederick Watts, Ray L Guttman, Mark Racette, Brad A Perlmutter, Joel S Ahmed, Anwar Shill, Holly A Singer, Carlos Goldwurm, Stefano Pezzoli, Gianni Zini, Michela Saint-Hilaire, Marie H Hendricks, Audrey E Williamson, Sally Nagle, Michael W Wilk, Jemma B Massood, Tiffany Huskey, Karen W Laramie, Jason M DeStefano, Anita L Baker, Kenneth B Itin, Ilia Litvan, Irene Nicholson, Garth Corbett, Alastair Nance, Martha Drasby, Edward Isaacson, Stuart Burn, David J Chinnery, Patrick F Pramstaller, Peter P Al-hinti, Jomana Moller, Anette T Ostergaard, Karen Sherman, Scott J Roxburgh, Richard Snow, Barry Slevin, John T Cambi, Franca Gusella, James F Myers, Richard H BMC Med Research Article BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. BioMed Central 2008-11-05 /pmc/articles/PMC2596771/ /pubmed/18986508 http://dx.doi.org/10.1186/1741-7015-6-32 Text en Copyright © 2008 Latourelle et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Latourelle, Jeanne C Sun, Mei Lew, Mark F Suchowersky, Oksana Klein, Christine Golbe, Lawrence I Mark, Margery H Growdon, John H Wooten, G Frederick Watts, Ray L Guttman, Mark Racette, Brad A Perlmutter, Joel S Ahmed, Anwar Shill, Holly A Singer, Carlos Goldwurm, Stefano Pezzoli, Gianni Zini, Michela Saint-Hilaire, Marie H Hendricks, Audrey E Williamson, Sally Nagle, Michael W Wilk, Jemma B Massood, Tiffany Huskey, Karen W Laramie, Jason M DeStefano, Anita L Baker, Kenneth B Itin, Ilia Litvan, Irene Nicholson, Garth Corbett, Alastair Nance, Martha Drasby, Edward Isaacson, Stuart Burn, David J Chinnery, Patrick F Pramstaller, Peter P Al-hinti, Jomana Moller, Anette T Ostergaard, Karen Sherman, Scott J Roxburgh, Richard Snow, Barry Slevin, John T Cambi, Franca Gusella, James F Myers, Richard H The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title | The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title_full | The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title_fullStr | The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title_full_unstemmed | The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title_short | The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study |
title_sort | gly2019ser mutation in lrrk2 is not fully penetrant in familial parkinson's disease: the genepd study |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596771/ https://www.ncbi.nlm.nih.gov/pubmed/18986508 http://dx.doi.org/10.1186/1741-7015-6-32 |
work_keys_str_mv | AT latourellejeannec thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT sunmei thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT lewmarkf thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT suchowerskyoksana thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT kleinchristine thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT golbelawrencei thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT markmargeryh thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT growdonjohnh thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wootengfrederick thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wattsrayl thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT guttmanmark thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT racettebrada thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT perlmutterjoels thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT ahmedanwar thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT shillhollya thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT singercarlos thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT goldwurmstefano thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT pezzoligianni thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT zinimichela thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT sainthilairemarieh thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT hendricksaudreye thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT williamsonsally thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT naglemichaelw thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wilkjemmab thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT massoodtiffany thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT huskeykarenw thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT laramiejasonm thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT destefanoanital thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT bakerkennethb thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT itinilia thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT litvanirene thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT nicholsongarth thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT corbettalastair thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT nancemartha thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT drasbyedward thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT isaacsonstuart thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT burndavidj thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT chinnerypatrickf thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT pramstallerpeterp thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT alhintijomana thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT molleranettet thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT ostergaardkaren thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT shermanscottj thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT roxburghrichard thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT snowbarry thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT slevinjohnt thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT cambifranca thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT gusellajamesf thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT myersrichardh thegly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT latourellejeannec gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT sunmei gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT lewmarkf gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT suchowerskyoksana gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT kleinchristine gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT golbelawrencei gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT markmargeryh gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT growdonjohnh gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wootengfrederick gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wattsrayl gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT guttmanmark gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT racettebrada gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT perlmutterjoels gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT ahmedanwar gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT shillhollya gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT singercarlos gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT goldwurmstefano gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT pezzoligianni gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT zinimichela gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT sainthilairemarieh gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT hendricksaudreye gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT williamsonsally gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT naglemichaelw gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT wilkjemmab gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT massoodtiffany gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT huskeykarenw gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT laramiejasonm gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT destefanoanital gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT bakerkennethb gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT itinilia gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT litvanirene gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT nicholsongarth gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT corbettalastair gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT nancemartha gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT drasbyedward gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT isaacsonstuart gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT burndavidj gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT chinnerypatrickf gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT pramstallerpeterp gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT alhintijomana gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT molleranettet gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT ostergaardkaren gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT shermanscottj gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT roxburghrichard gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT snowbarry gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT slevinjohnt gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT cambifranca gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT gusellajamesf gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy AT myersrichardh gly2019sermutationinlrrk2isnotfullypenetrantinfamilialparkinsonsdiseasethegenepdstudy |