title: Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease.
abstract: Leucine-rich repeat kinase 1 gene (LRRK1) on chromosome 15q26.3 is a paralog of LRRK2 in which multiple substitutions were recently linked to Parkinson's disease. We have examined the exon-intron structure of the gene and the expressed mRNA sequence in brain. LRRK1 sequencing analysis in 95 probands from families with autosomal dominant Parkinson's disease identified 23 variants, 14 of which are novel, with four resulting in non-synonymous amino acid substitutions. These four substitutions are rare and do not clearly segregate with disease within our families or associate with sporadic Parkinson's disease in a US case-control series. Subsequent sequencing of exon 26 encoding the kinase activation segment in an additional 360 probands identified one further synonymous variant, suggesting that LRRK1 variants are not a frequent cause of Parkinson's disease. The relative absence of substitutions within LRRK1 highlights a greater conservation of sequence than observed for LRRK2. Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Julie P
authors.initials: JP
authors.lastname: Taylor
authors.forename: Mary M
authors.initials: MM
authors.lastname: Hulihan
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kachergus
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Hinkle
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Stone
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Robert
authors.initials: R
authors.lastname: Hauser
authors.forename: Jan
authors.initials: J
authors.lastname: Aasly
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Haydeh
authors.initials: H
authors.lastname: Payami
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020029:Base Pairing; D001483:Base Sequence; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C510751:LRRK1 protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases