title: LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8.
abstract: BACKGROUND
  Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been found to cause typical, later-onset Parkinson disease (PD). Although G2019S is the most common mutation, other mutations have also been reported. It is critical to catalog the types of mutations found in LRRK2 that can cause PD, so as to provide insight regarding disease susceptibility and potential novel treatments.
  
  
  METHODS
  We performed a comprehensive study of all 51 exons of the LRRK2 gene in one PD patient from each of 88 multiplex PD families who had the highest family-specific multipoint lod score at the LRRK2 locus from a cohort of 430 PD families without the G2019S mutation.
  
  
  RESULTS
  Five families (5.7%) harbored what seem to be novel, pathogenic mutations (L1795F, I1192V, E10K, E334K, Q1111H). Three of these apparent mutations were in known, functional domains of the LRRK2 protein, where other studies have also identified disease producing mutations. However, two of the novel variants were found in the N-terminal region of LRRK2, where no pathogenic substitutions have yet been reported. Similar to previous studies, all subjects with an LRRK2 mutation had classic symptoms of PD and typical, later age at onset.
  
  
  CONCLUSIONS
  We have identified five novel variants in LRRK2, with two of these in the N-terminal region of LRRK2, where no pathogenic substitutions have been previously reported. If confirmed to be causative, these mutations would broaden the potential mechanisms whereby mutations in LRRK2 result in Parkinson disease.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA. bill.nichols@cchmc.org
authors.forename: W C
authors.initials: WC
authors.lastname: Nichols
authors.forename: V E
authors.initials: VE
authors.lastname: Elsaesser
authors.forename: N
authors.initials: N
authors.lastname: Pankratz
authors.forename: M W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: D K
authors.initials: DK
authors.lastname: Marek
authors.forename: C A
authors.initials: CA
authors.lastname: Halter
authors.forename: A
authors.initials: A
authors.lastname: Rudolph
authors.forename: C W
authors.initials: CW
authors.lastname: Shults
authors.forename: T
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*