TY - JOUR
T1 - Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients
AU - Nuytemans, Karen
AU - Rademakers, Rosa
AU - Theuns, Jessie
AU - Pals, Philippe
AU - Engelborghs, Sebastiaan
AU - Pickut, Barbara
AU - de Pooter, Tim
AU - Peeters, Karin
AU - Mattheijssens, Maria
AU - Van den Broeck, Marleen
AU - Cras, Patrick
AU - De Deyn, Peter Paul
AU - van Broeckhoven, Christine
N1 - Funding Information:
We are grateful to the participants of this study for their kind cooperation and to the personnel of the VIB – Genetic Service Facility (http://www.vibgeneticservicefacility.be) and the Biobank of the Institute Born-Bunge. This research was supported by the Special Research Fund of the University of Antwerp, the Fund for Scientific Research Flanders (FWO-F), the Institute for Science and Technology – Flanders (IWT-F) to CVB, the Medical Research Foundation Antwerp and Neurosearch Antwerp to PPDD and the Interuniversity Attraction Poles program P6/43 of the Belgian Science Policy Office (CVB and PPDD). The IWT-F provided a PhD fellowship to KN; RR, JT and SE are holders of a postdoctoral fellowship of FWO-F, Belgium.
PY - 2008/4
Y1 - 2008/4
N2 - 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 438kb, 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.
AB - 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 438kb, 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.
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U2 - 10.1038/sj.ejhg.5201986
DO - 10.1038/sj.ejhg.5201986
M3 - Article
C2 - 18197194
AN - SCOPUS:41049086705
SN - 1018-4813
VL - 16
SP - 471
EP - 479
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 4
ER -