Rare variants in LRRK1 and Parkinson's disease.
Approximately 20 % of individuals with Parkinson's disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset PD to identify 15 potentially causal variants. Segregation analysis and frequency assessment in 862 PD cases and 1,014 ethnically matched controls highlighted variants in EEF1D and LRRK1 as the best candidates. Mutation screening of the coding regions of these genes in 862 cases and 1,014 controls revealed several novel non-synonymous variants in both genes in cases and controls. An in silico multi-model bioinformatics analysis was used to prioritize identified variants in LRRK1 for functional follow-up. However, protein expression, subcellular localization, and cell viability were not affected by the identified variants. Although it has yet to be proven conclusively that variants in LRRK1 are indeed causative of PD, our data strengthen a possible role for LRRK1 in addition to LRRK2 in the genetic underpinnings of PD but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance.
Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675, Munich, Germany.
Eva C
EC
Schulte
Daniel C
DC
Ellwanger
Sybille
S
Dihanich
Claudia
C
Manzoni
Katrin
K
Stangl
Barbara
B
Schormair
Elisabeth
E
Graf
Sebastian
S
Eck
Brit
B
Mollenhauer
Dietrich
D
Haubenberger
Walter
W
Pirker
Alexander
A
Zimprich
Thomas
T
Brücke
Peter
P
Lichtner
Annette
A
Peters
Christian
C
Gieger
Claudia
C
Trenkwalder
Hans-Werner
HW
Mewes
Thomas
T
Meitinger
Patrick A
PA
Lewis
Hans H
HH
Klünemann
Juliane
J
Winkelmann
D000465:Algorithms; D002470:Cell Survival; D004252:DNA Mutational Analysis; D059472:Exome; D005192:Family Health; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000235:genetics*; D020648:Peptide Elongation Factor 1 / Q000235:genetics; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
C000591363:EEF1D protein, human; D020648:Peptide Elongation Factor 1; C510751:LRRK1 protein, human; D017346:Protein Serine-Threonine Kinases