title: R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation.
abstract: Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. bill.nichols@cchmc.org
authors.forename: William C
authors.initials: WC
authors.lastname: Nichols
authors.forename: Diane K
authors.initials: DK
authors.lastname: Marek
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pauciulo
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Halter
authors.forename: Alice
authors.initials: A
authors.lastname: Rudolph
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Shults
authors.forename: Joanne
authors.initials: J
authors.lastname: Wojcieszek
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D033741:Adenine Nucleotide Translocator 1; D002352:Carrier Proteins; C037853:glutamine transport proteins; D001120:Arginine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases