Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease: The genePD study

Mei Sun, Jeanne C. Latourelle, G. Frederick Wooten, Mark F. Lew, Christine Klein, Holly A. Shill, Lawrence I. Golbe, Margery H. Mark, Brad A. Racette, Joel S. Perlmutter, Abbas Parsian, Mark Guttman, Garth Nicholson, Gang Xu, Jemma B. Wilk, Marie H. Saint-Hilaire, Anita L. DeStefano, Ranjana Prakash, Sally Williamson, Oksana SuchowerskyNancy Labelle, John H. Growdon, Carlos Singer, Ray L. Watts, Stefano Goldwurm, Gianni Pezzoli, Kenneth B. Baker, Peter P. Pramstaller, David J. Burn, Patrick F. Chinnery, Scott J Sherman, Peter Vieregge, Irene Litvan, Tammy Gillis, Marcy E. MacDonald, Richard H. Myers, James F. Gusella

Research output: Contribution to journalArticle

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Abstract

Background: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design: Clinical and genetic study. Setting: Twenty collaborative clinical sites. Patients: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. Main Outcome Measures: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results: Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P=.04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P=.04). Conclusions: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

Original languageEnglish (US)
Pages (from-to)826-832
Number of pages7
JournalArchives of Neurology
Volume63
Issue number6
DOIs
StatePublished - 2006

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Age of Onset
Parkinson Disease
Mutation
Heterozygote
Point Mutation
Exons
Familial
Onset
Parkinson's Disease
Genes
Insertional Mutagenesis
Homozygote
Parkinsonian Disorders
Siblings
Alleles
Outcome Assessment (Health Care)
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sun, M., Latourelle, J. C., Wooten, G. F., Lew, M. F., Klein, C., Shill, H. A., ... Gusella, J. F. (2006). Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease: The genePD study. Archives of Neurology, 63(6), 826-832. https://doi.org/10.1001/archneur.63.6.826

Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease : The genePD study. / Sun, Mei; Latourelle, Jeanne C.; Wooten, G. Frederick; Lew, Mark F.; Klein, Christine; Shill, Holly A.; Golbe, Lawrence I.; Mark, Margery H.; Racette, Brad A.; Perlmutter, Joel S.; Parsian, Abbas; Guttman, Mark; Nicholson, Garth; Xu, Gang; Wilk, Jemma B.; Saint-Hilaire, Marie H.; DeStefano, Anita L.; Prakash, Ranjana; Williamson, Sally; Suchowersky, Oksana; Labelle, Nancy; Growdon, John H.; Singer, Carlos; Watts, Ray L.; Goldwurm, Stefano; Pezzoli, Gianni; Baker, Kenneth B.; Pramstaller, Peter P.; Burn, David J.; Chinnery, Patrick F.; Sherman, Scott J; Vieregge, Peter; Litvan, Irene; Gillis, Tammy; MacDonald, Marcy E.; Myers, Richard H.; Gusella, James F.

In: Archives of Neurology, Vol. 63, No. 6, 2006, p. 826-832.

Research output: Contribution to journalArticle

Sun, M, Latourelle, JC, Wooten, GF, Lew, MF, Klein, C, Shill, HA, Golbe, LI, Mark, MH, Racette, BA, Perlmutter, JS, Parsian, A, Guttman, M, Nicholson, G, Xu, G, Wilk, JB, Saint-Hilaire, MH, DeStefano, AL, Prakash, R, Williamson, S, Suchowersky, O, Labelle, N, Growdon, JH, Singer, C, Watts, RL, Goldwurm, S, Pezzoli, G, Baker, KB, Pramstaller, PP, Burn, DJ, Chinnery, PF, Sherman, SJ, Vieregge, P, Litvan, I, Gillis, T, MacDonald, ME, Myers, RH & Gusella, JF 2006, 'Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease: The genePD study', Archives of Neurology, vol. 63, no. 6, pp. 826-832. https://doi.org/10.1001/archneur.63.6.826
Sun, Mei ; Latourelle, Jeanne C. ; Wooten, G. Frederick ; Lew, Mark F. ; Klein, Christine ; Shill, Holly A. ; Golbe, Lawrence I. ; Mark, Margery H. ; Racette, Brad A. ; Perlmutter, Joel S. ; Parsian, Abbas ; Guttman, Mark ; Nicholson, Garth ; Xu, Gang ; Wilk, Jemma B. ; Saint-Hilaire, Marie H. ; DeStefano, Anita L. ; Prakash, Ranjana ; Williamson, Sally ; Suchowersky, Oksana ; Labelle, Nancy ; Growdon, John H. ; Singer, Carlos ; Watts, Ray L. ; Goldwurm, Stefano ; Pezzoli, Gianni ; Baker, Kenneth B. ; Pramstaller, Peter P. ; Burn, David J. ; Chinnery, Patrick F. ; Sherman, Scott J ; Vieregge, Peter ; Litvan, Irene ; Gillis, Tammy ; MacDonald, Marcy E. ; Myers, Richard H. ; Gusella, James F. / Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease : The genePD study. In: Archives of Neurology. 2006 ; Vol. 63, No. 6. pp. 826-832.
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title = "Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease: The genePD study",
abstract = "Background: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design: Clinical and genetic study. Setting: Twenty collaborative clinical sites. Patients: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. Main Outcome Measures: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results: Mutations were found in 23 families (12.6{\%} of those screened). Among the mutation-positive families, 10 (43{\%}) contained compound heterozygotes; 3 (13{\%}), homozygotes; and 10 (43{\%}), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P=.04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P=.04). Conclusions: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.",
author = "Mei Sun and Latourelle, {Jeanne C.} and Wooten, {G. Frederick} and Lew, {Mark F.} and Christine Klein and Shill, {Holly A.} and Golbe, {Lawrence I.} and Mark, {Margery H.} and Racette, {Brad A.} and Perlmutter, {Joel S.} and Abbas Parsian and Mark Guttman and Garth Nicholson and Gang Xu and Wilk, {Jemma B.} and Saint-Hilaire, {Marie H.} and DeStefano, {Anita L.} and Ranjana Prakash and Sally Williamson and Oksana Suchowersky and Nancy Labelle and Growdon, {John H.} and Carlos Singer and Watts, {Ray L.} and Stefano Goldwurm and Gianni Pezzoli and Baker, {Kenneth B.} and Pramstaller, {Peter P.} and Burn, {David J.} and Chinnery, {Patrick F.} and Sherman, {Scott J} and Peter Vieregge and Irene Litvan and Tammy Gillis and MacDonald, {Marcy E.} and Myers, {Richard H.} and Gusella, {James F.}",
year = "2006",
doi = "10.1001/archneur.63.6.826",
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pages = "826--832",
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TY - JOUR

T1 - Influence of heterozygosity for Parkin mutation on onset age in familial parkinson disease

T2 - The genePD study

AU - Sun, Mei

AU - Latourelle, Jeanne C.

AU - Wooten, G. Frederick

AU - Lew, Mark F.

AU - Klein, Christine

AU - Shill, Holly A.

AU - Golbe, Lawrence I.

AU - Mark, Margery H.

AU - Racette, Brad A.

AU - Perlmutter, Joel S.

AU - Parsian, Abbas

AU - Guttman, Mark

AU - Nicholson, Garth

AU - Xu, Gang

AU - Wilk, Jemma B.

AU - Saint-Hilaire, Marie H.

AU - DeStefano, Anita L.

AU - Prakash, Ranjana

AU - Williamson, Sally

AU - Suchowersky, Oksana

AU - Labelle, Nancy

AU - Growdon, John H.

AU - Singer, Carlos

AU - Watts, Ray L.

AU - Goldwurm, Stefano

AU - Pezzoli, Gianni

AU - Baker, Kenneth B.

AU - Pramstaller, Peter P.

AU - Burn, David J.

AU - Chinnery, Patrick F.

AU - Sherman, Scott J

AU - Vieregge, Peter

AU - Litvan, Irene

AU - Gillis, Tammy

AU - MacDonald, Marcy E.

AU - Myers, Richard H.

AU - Gusella, James F.

PY - 2006

Y1 - 2006

N2 - Background: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design: Clinical and genetic study. Setting: Twenty collaborative clinical sites. Patients: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. Main Outcome Measures: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results: Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P=.04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P=.04). Conclusions: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

AB - Background: The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). Objective: To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Design: Clinical and genetic study. Setting: Twenty collaborative clinical sites. Patients: Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. Main Outcome Measures: Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Results: Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P=.04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P=.04). Conclusions: These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

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