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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...

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Autores principales: 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
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
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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.
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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
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