title: Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients.
abstract: We determined the prevalence of mutations in two major functional domains of the leucine-rich repeat kinase 2 gene (LRRK2) in Belgian Parkinson's disease (PD) patients (N=304) of which 18.1% were familial PD patients. Ten patients were heterozygous for five different missense mutations (3.29%) of whom six carried the same mutation p.R1441C (1.97%). All six p.R1441C carriers were familial PD patients explaining 10.7% of familial PD in the Belgian patient group. Moreover, they shared a common disease haplotype of 21 consecutive markers in a region of 438 kb, suggesting that they are distant descendants of a single common ancestor. Clinically, p.R1441C carriers had typical levodopa-responsive parkinsonism with tremor as the most common presenting feature. Their age at onset was highly variable and ranged from 39 to 73 years, suggesting the influence of modifying factors. The remaining four patients were heterozygous each for a novel missense mutation located in the Roc or kinase domain. The pathogenic nature of these mutations remains to be determined, though we have genetic evidence that at least some represent rare but benign variants rather than causal mutations. The latter observation indicates that prudence is needed in diagnostic testing of LRRK2 in PD patients. Functional data should underlie a conclusion on the pathogenic nature of some mutations that have not been conclusively linked to disease.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Nuytemans
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Philippe
authors.initials: P
authors.lastname: Pals
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Barbara
authors.initials: B
authors.lastname: Pickut
authors.forename: Tim
authors.initials: T
authors.lastname: de Pooter
authors.forename: Karin
authors.initials: K
authors.lastname: Peeters
authors.forename: Maria
authors.initials: M
authors.lastname: Mattheijssens
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Christine
authors.initials: C
authors.lastname: van Broeckhoven
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000595:Amino Acid Sequence; D001530:Belgium; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases