title: The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease.
abstract: OBJECTIVE
  To study the possible association of founder mutations in the lysosomal storage disorder genes HEXA, SMPD1, and MCOLN1 (causing Tay-Sachs, Niemann-Pick A, and mucolipidosis type IV diseases, respectively) with Parkinson disease (PD).
  
  
  METHODS
  Two PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that included a total of 938 patients, were studied: a cohort of 654 patients from Tel Aviv, and a replication cohort of 284 patients from New York. Eight AJ founder mutations in the HEXA, SMPD1, and MCOLN1 genes were analyzed. The frequencies of these mutations were compared to AJ control groups that included large published groups undergoing prenatal screening and 282 individuals matched for age and sex.
  
  
  RESULTS
  Mutation frequencies were similar in the 2 groups of patients with PD. The SMPD1 p.L302P was strongly associated with a highly increased risk for PD (odds ratio 9.4, 95% confidence interval 3.9-22.8, p < 0.0001), as 9/938 patients with PD were carriers of this mutation compared to only 11/10,709 controls.
  
  
  CONCLUSIONS
  The SMPD1 p.L302P mutation is a novel risk factor for PD. Although it is rare on a population level, the identification of this mutation as a strong risk factor for PD may further elucidate PD pathogenesis and the role of lysosomal pathways in disease development.
authors.affiliation: Genetic Institute and Movement Disorders Unit, Parkinson Center, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gan-Or
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.forename: Anat
authors.initials: A
authors.lastname: Bar-Shira
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
authors.forename: Ruth
authors.initials: R
authors.lastname: Kornreich
authors.forename: Mali
authors.initials: M
authors.lastname: Gana-Weisz
authors.forename: Deborah
authors.initials: D
authors.lastname: Raymond
authors.forename: Liron
authors.initials: L
authors.lastname: Rozenkrantz
authors.forename: Andres
authors.initials: A
authors.lastname: Deik
authors.forename: Tanya
authors.initials: T
authors.lastname: Gurevich
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Gross
authors.forename: Nicole
authors.initials: N
authors.lastname: Schreiber-Agus
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.forename: Susan B
authors.initials: SB
authors.lastname: Bressman
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
mesh_terms: D000368:Aged; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*
chemical_list: C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase
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