Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.
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.
Di Fonzo
Alessio
A
Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
Tassorelli
Cristina
C
De Mari
Michele
M
Chien
Hsin F
HF
Ferreira
Joaquim
J
Rohé
Christan F
CF
Riboldazzi
Giulio
G
Antonini
Angelo
A
Albani
Gianni
G
Mauro
Alessandro
A
Marconi
Roberto
R
Abbruzzese
Giovanni
G
Lopiano
Leonardo
L
Fincati
Emiliana
E
Guidi
Marco
M
Marini
Paolo
P
Stocchi
Fabrizio
F
Onofrj
Marco
M
Toni
Vincenzo
V
Tinazzi
Michele
M
Fabbrini
Giovanni
G
Lamberti
Paolo
P
Vanacore
Nicola
N
Meco
Giuseppe
G
Leitner
Petra
P
Uitti
Ryan J
RJ
Wszolek
Zbigniew K
ZK
Gasser
Thomas
T
Simons
Erik J
EJ
Breedveld
Guido J
GJ
Goldwurm
Stefano
S
Pezzoli
Gianni
G
Sampaio
Cristina
C
Barbosa
Egberto
E
Martignoni
Emilia
E
Oostra
Ben A
BA
Bonifati
Vincenzo
V
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
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases