title: Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
abstract: Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.
authors.affiliation: Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
authors.forename: Alessio
authors.initials: A
authors.lastname: Di Fonzo
authors.forename: Cristina
authors.initials: C
authors.lastname: Tassorelli
authors.forename: Michele
authors.initials: M
authors.lastname: De Mari
authors.forename: Hsin F
authors.initials: HF
authors.lastname: Chien
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ferreira
authors.forename: Christan F
authors.initials: CF
authors.lastname: Rohé
authors.forename: Giulio
authors.initials: G
authors.lastname: Riboldazzi
authors.forename: Angelo
authors.initials: A
authors.lastname: Antonini
authors.forename: Gianni
authors.initials: G
authors.lastname: Albani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.forename: Roberto
authors.initials: R
authors.lastname: Marconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbruzzese
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lopiano
authors.forename: Emiliana
authors.initials: E
authors.lastname: Fincati
authors.forename: Marco
authors.initials: M
authors.lastname: Guidi
authors.forename: Paolo
authors.initials: P
authors.lastname: Marini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Stocchi
authors.forename: Marco
authors.initials: M
authors.lastname: Onofrj
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Toni
authors.forename: Michele
authors.initials: M
authors.lastname: Tinazzi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fabbrini
authors.forename: Paolo
authors.initials: P
authors.lastname: Lamberti
authors.forename: Nicola
authors.initials: N
authors.lastname: Vanacore
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meco
authors.forename: Petra
authors.initials: P
authors.lastname: Leitner
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Simons
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Cristina
authors.initials: C
authors.lastname: Sampaio
authors.forename: Egberto
authors.initials: E
authors.lastname: Barbosa
authors.forename: Emilia
authors.initials: E
authors.lastname: Martignoni
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D018450:Disease Progression; D005091:Exons; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases