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

Persistent Link:
http://hdl.handle.net/10150/610045
Title:
The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study
Author:
Latourelle, Jeanne; Sun, Mei; Lew, Mark; Suchowersky, Oksana; Klein, Christine; Golbe, Lawrence; Mark, Margery; Growdon, John; Wooten, G. F.; Watts, Ray; Guttman, Mark; Racette, Brad; Perlmutter, Joel; Ahmed, Anwar; Shill, Holly; Singer, Carlos; Goldwurm, Stefano; Pezzoli, Gianni; Zini, Michela; Saint-Hilaire, Marie; Hendricks, Audrey; Williamson, Sally; Nagle, Michael; Wilk, Jemma; Massood, Tiffany; Huskey, Karen; Laramie, Jason; DeStefano, Anita; Baker, Kenneth; Itin, Ilia
Affiliation:
Department of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USA; Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA; Department of Neurology, University of Southern California, Los Angeles, CA, USA; Departments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canada; Department of Neurology, Medical University of Lübeck, Lübeck, Germany; Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School Boston, MA, USA; Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Toronto, Toronto, Canada; Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA; Barrow Neurological Institute, Phoenix, AZ, USA; Sun Health Research Institute, Sun City, AZ, USA; Department of Neurology, University of Miami, Miami, FL, USA; Parkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italy; Department of Biostatistics, Boston University School of Medicine, Boston University, Boston, MA, USA; Departments of Neurology and Neuroscience, Cleveland Clinic Foundation, Cleveland, OH, USA; Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA; Neurology Department, University of Sydney ANZAC Research Institute, Concord Hospital, Sydney, Australia; Struthers Parkinson's Center, Park Nicollet Clinic, Golden Valley, MN, USA; Port City Neurology, Scarborough, ME, USA; Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL, USA; Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK; Regional Neurosciences Centre, Newcastle University, Newcastle upon Tyne, UK; Department of Neurology, General Regional Hospital Bolzano, Bolzano, Italy; Department of Neurology, University of Arkansas for Medical Sciences, AR, USA; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, University of Arizona, Tucson, AZ, USA; Department of Neurology, Auckland City Hospital, Auckland, New Zealand; Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA
Issue Date:
2008
Publisher:
BioMed Central
Citation:
BMC Medicine 2008, 6:32 doi:10.1186/1741-7015-6-32
Journal:
BMC Medicine
Rights:
© 2008 Latourelle et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
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.
EISSN:
1741-7015
DOI:
10.1186/1741-7015-6-32
Version:
Final published version
Additional Links:
http://www.biomedcentral.com/1741-7015/6/32

Full metadata record

DC FieldValue Language
dc.contributor.authorLatourelle, Jeanneen
dc.contributor.authorSun, Meien
dc.contributor.authorLew, Marken
dc.contributor.authorSuchowersky, Oksanaen
dc.contributor.authorKlein, Christineen
dc.contributor.authorGolbe, Lawrenceen
dc.contributor.authorMark, Margeryen
dc.contributor.authorGrowdon, Johnen
dc.contributor.authorWooten, G. F.en
dc.contributor.authorWatts, Rayen
dc.contributor.authorGuttman, Marken
dc.contributor.authorRacette, Braden
dc.contributor.authorPerlmutter, Joelen
dc.contributor.authorAhmed, Anwaren
dc.contributor.authorShill, Hollyen
dc.contributor.authorSinger, Carlosen
dc.contributor.authorGoldwurm, Stefanoen
dc.contributor.authorPezzoli, Giannien
dc.contributor.authorZini, Michelaen
dc.contributor.authorSaint-Hilaire, Marieen
dc.contributor.authorHendricks, Audreyen
dc.contributor.authorWilliamson, Sallyen
dc.contributor.authorNagle, Michaelen
dc.contributor.authorWilk, Jemmaen
dc.contributor.authorMassood, Tiffanyen
dc.contributor.authorHuskey, Karenen
dc.contributor.authorLaramie, Jasonen
dc.contributor.authorDeStefano, Anitaen
dc.contributor.authorBaker, Kennethen
dc.contributor.authorItin, Iliaen
dc.date.accessioned2016-05-20T08:57:18Z-
dc.date.available2016-05-20T08:57:18Z-
dc.date.issued2008en
dc.identifier.citationBMC Medicine 2008, 6:32 doi:10.1186/1741-7015-6-32en
dc.identifier.doi10.1186/1741-7015-6-32en
dc.identifier.urihttp://hdl.handle.net/10150/610045-
dc.description.abstractBACKGROUND: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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://www.biomedcentral.com/1741-7015/6/32en
dc.rights© 2008 Latourelle et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.titleThe Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD studyen
dc.typeArticleen
dc.identifier.eissn1741-7015en
dc.contributor.departmentDepartment of Neurology, Boston University School of Medicine, Boston University, Boston, MA, USAen
dc.contributor.departmentMolecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School Boston, MA, USAen
dc.contributor.departmentDepartment of Neurology, University of Southern California, Los Angeles, CA, USAen
dc.contributor.departmentDepartments of Clinical Neurosciences and Medical Genetics, University of Calgary, Calgary, Alberta, Canadaen
dc.contributor.departmentDepartment of Neurology, Medical University of Lübeck, Lübeck, Germanyen
dc.contributor.departmentDepartment of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ, USAen
dc.contributor.departmentDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School Boston, MA, USAen
dc.contributor.departmentDepartment of Neurology, University of Virginia Health System, Charlottesville, VA, USAen
dc.contributor.departmentDepartment of Neurology, University of Alabama at Birmingham, Birmingham, AL, USAen
dc.contributor.departmentDepartment of Medicine, University of Toronto, Toronto, Canadaen
dc.contributor.departmentDepartment of Neurology, Washington University School of Medicine, Saint Louis, MO, USAen
dc.contributor.departmentBarrow Neurological Institute, Phoenix, AZ, USAen
dc.contributor.departmentSun Health Research Institute, Sun City, AZ, USAen
dc.contributor.departmentDepartment of Neurology, University of Miami, Miami, FL, USAen
dc.contributor.departmentParkinson Institute, Istituti Clinici di Perfezionamento, Milano, Italyen
dc.contributor.departmentDepartment of Biostatistics, Boston University School of Medicine, Boston University, Boston, MA, USAen
dc.contributor.departmentDepartments of Neurology and Neuroscience, Cleveland Clinic Foundation, Cleveland, OH, USAen
dc.contributor.departmentDepartment of Neurology, University of Louisville School of Medicine, Louisville, KY, USAen
dc.contributor.departmentNeurology Department, University of Sydney ANZAC Research Institute, Concord Hospital, Sydney, Australiaen
dc.contributor.departmentStruthers Parkinson's Center, Park Nicollet Clinic, Golden Valley, MN, USAen
dc.contributor.departmentPort City Neurology, Scarborough, ME, USAen
dc.contributor.departmentParkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL, USAen
dc.contributor.departmentInstitute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UKen
dc.contributor.departmentRegional Neurosciences Centre, Newcastle University, Newcastle upon Tyne, UKen
dc.contributor.departmentDepartment of Neurology, General Regional Hospital Bolzano, Bolzano, Italyen
dc.contributor.departmentDepartment of Neurology, University of Arkansas for Medical Sciences, AR, USAen
dc.contributor.departmentDepartment of Neurology, Aarhus University Hospital, Aarhus, Denmarken
dc.contributor.departmentDepartment of Neurology, University of Arizona, Tucson, AZ, USAen
dc.contributor.departmentDepartment of Neurology, Auckland City Hospital, Auckland, New Zealanden
dc.contributor.departmentDepartment of Neurology, University of Kentucky College of Medicine, Lexington, KY, USAen
dc.identifier.journalBMC Medicineen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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