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J Neurol Neurosurg Psychiatry. 2006 July; 77(7): 891–892.
PMCID: PMC2117481

The LRRK2 gene in Parkinson's disease: mutation screening in patients from Germany

Since the identification in 2004 of mutations within the leucine‐rich repeat kinase 2 (LRRK2) gene in patients with autosomal, dominantly inherited Parkinson's disease, this gene has been the focus of research on Parkinson's disease.1 Mutations in the LRRK2 gene and especially the common mutation G2019S may account for 1–2% of familial and 3–6% of sporadic cases of Parkinson's disease, including those of early and late onset.2 The LRRK2 gene is situated on chromosome 12p11.2–q13.1 and encodes a large protein named dardarin. Dardarin contains several functional domains, including a leucine‐rich repeat domain, WD40, renin–angiotensin system/guanosine triphosphatases and kinase domains. The presence of the leucine‐rich repeat and WD40 domains suggests a role in protein–protein interaction. In addition, function was demonstrated kinase for dardarin in vitro.3

Some questions remain about the growing demand of DNA diagnostics and genetic counselling in Parkinson's disease. Which subpopulation of patients with Parkinson's disease harbours the highest risk of mutations in the LRRK2 gene? What is the frequency and penetrance of different LRRK2 mutations? Nine exons (exons 19, 24, 25, 29, 31, 34, 35, 38 and 41) of the LRRK2 gene were screened for sequence variations in a cohort of 120 patients (mean age at onset 56.3 years). The cohort was recruited in Germany and consisted of 10 (8%) patients with early‐onset (age at onset <45 years) and 110 (92%) patients with late‐onset Parkinson's disease. Approximately 25.8% of the patients had a family history of Parkinson's disease. Screening was carried out by PCR, denaturating high‐performance liquid chromatography and direct DNA sequencing. The ethics committee of Ruhr‐University Bochum, Bochum, Germany, approved this study. More detailed information and primer sequences are available from the authors upon request.

Several common exonic (G1624G, K1637K, S1647T) exchanges and intronic single‐nucleotide polymorphisms (Ivs33‐31T>C, Ivs34+32A>G, Ivs34‐51A>T, Ivs35+23T>A, Ivs38+35G>A) were identified. Of three (2.5%) patients who carried mutations in heterozygous state, two harboured the common mutation G2019S (age at onset 30 and 44 years) and one patient showed a novel mutation A1151T (age at onset 55 years).

To optimise future genetic testing and counselling, we aimed at identifying patient phenotypes with the highest risk for mutations in the LRRK2 gene in Germany. The patients represent a cohort with sporadic and familial, early‐onset and late‐onset Parkinson's disease. In our study, three (2.5%) patients carried LRRK2 mutations (G2019S, A1151T). This frequency may even be an underestimation of LRRK2 mutations, because our screening was limited to 9 of the 51 exons of the gene. In all, 6.7% of the patients with a family history of Parkinson's disease and 1.1% of the patients with sporadic Parkinson's disease are mutation carriers. Patients with early‐onset Parkinson's disease may have the highest risk for mutation in the LRRK2 gene: 2 of the 10 patients with early‐onset Parkinson's disease but only 1 of the 110 patients with late‐onset Parkinson's disease harbour a mutation. Further investigations with larger cohorts are needed to verify the observed tendencies.

The novel mutation A1151T was identified in a patient with late‐onset Parkinson's disease (onset at 55 years). The patient's mother died at the age of 68 years and her father at the age of 30 years. Thus it remains unclear whether the mutation is fully penetrant or has appeared de novo and whether the parents died before manifestation of the disease. The mutation was not observed in 336 ethnically but not age‐matched control chromosomes of senior healthy blood donors from Germany. The A1151T mutation is located within the leucine‐rich repeat domain (fig 11).). Although the pathogenicity is not yet confirmed, conservation of the A1151 residue lends some support to the hypothesis that the A1151T exchange may be causally related to Parkinson's disease. Onset of the disease in this patient occurred at the age of 55 years, with resting tremor in the left hand and akinesis. After a disease duration of 10 years, the patient has distinct on–off fluctuation and mild cognitive impairment.

figure jn83022.f1
Figure 1 Structure of the leucine‐rich repeat kinase 2 protein and functional domains: leucine‐rich repeat (LRR), renin–angiotensin system in complex (ROC) proteins, C‐terminal domain of ROC (COR), mitogen‐activated ...

Two patients carried the common G2019S mutation in heterozygous state. The mutation was not observed in 336 ethnically matched control chromosomes of senior healthy blood donors from Germany. To date, the mutation has been found in only one of more than 4000 healthy controls of different ethnic backgrounds.4 One mutation carrier of German origin has typical, asymmetric, levadopa‐responsive early‐onset Parkinson's disease (age at onset 44 years). He reported that his father had tremors. DNA and neurological examination of the patient's father were impossible. The other mutation carrier from Belarus had early‐onset Parkinson's disease (age at onset 30 years) dominated by akinesis and rigors. Besides the early manifestation of the disease, no other atypical features were observed. In her great grandmother, Parkinson's disease, with tremor and manifestation in her 70s, has been reported. Her mother is also a mutation carrier in heterozygous state, but remains asymptomatic (clinical examination) at 68 years. The question arises whether the mutation is incompletely penetrant or whether the manifestation is age dependent. Discordant findings in monozygotic twins favour the hypotheses of environmental modifiers.5 Taken together, our findings support the hypothesis of a complex interplay between genetic and environmental factors in the pathogenesis of Parkinson's disease. The hypothesis of incomplete penetrance is supported by an unaffected 89‐year‐old with a G2019S mutation.4

Acknowledgements

We thank all the participants in this study. AMS acknowledges a fellowship from the Alma and Heinrich Vogelsang Foundation.

Footnotes

Competing interests: none declared

References

1. Paisan‐Ruiz C, Jain S, Evans E W. et al Cloning of the gene containing mutations that cause PARK8‐linked Parkinson's disease. Neuron 2004. 44595–600.600. [PubMed]
2. Gilks W P, Abou‐Sleiman P M, Gandhi S. et al A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005. 365415–416.416. [PubMed]
3. Shen J. Protein kinases linked to the pathogenesis of Parkinson's disease. Neuron 2004. 44575–577.577. [PubMed]
4. Kay D M, Kramer P, Higgins D. et al Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005. 201077–1078.1078. [PubMed]
5. Singleton A B. Altered alpha‐synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin. Trends Neurosci 2005. 28416–421.421. [PubMed]

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