Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients

• Published in: European journal of human genetics : EJHG Vol. 16; no. 4; pp. 471 - 479
• Main Authors: NUYTEMANS, Karen, RADEMAKERS, Rosa, CRAS, Patrick, DE DEYN, Peter Paul, VAN BROECKHOVEN, Christine, THEUNS, Jessie, PALS, Philippe, ENGELBORGHS, Sebastiaan, PICKUT, Barbara, DE POOTER, Tim, PEETERS, Karin, MATTHEIJSSENS, Maria, VAN DEN BROECK, Marleen
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing 01.04.2008; Nature Publishing Group
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Amino Acid Sequence; Basal ganglia; Belgium; Benign; Biological and medical sciences; Brain diseases; Central nervous system diseases; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dementia; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Human; Humans; Kinases; Leucine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; LRRK2 protein; Male; Medical genetics; Medical sciences; Middle Aged; Missense mutation; Molecular and cellular biology; Molecular Sequence Data; Movement disorders; Mutation; Mutation - genetics; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Parkinson Disease - genetics; Parkinson's disease; Pedigree; Population genetics, reproduction patterns; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Proteins; Sequence Alignment; Studies; Tremor; Belgium; Human; Nervous system diseases; Parkinson's disease; Enzyme; Repeated sequence; Transferases; LRRK2; Parkinson disease; Patient; p.R1441C founder mutation; Leucine; Founder effect; Cerebral disorder; Gene; Kinase; Aminoacid; Central nervous system disease; Genetics; Degenerative disease; Mutation; Extrapyramidal syndrome
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/sj.ejhg.5201986

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.