Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW.
A common LRRK2 mutation in idiopathic Parkinson's disease.
Lancet. 2005 Jan 29-Feb 4;365(9457):415-6.
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These papers show that the G2019S mutation in LRRK2/dardarin is the most common single gene mutation associated with PD. Assuming that the change is pathogenic, this is an astounding result and would account for around 5 percent of cases with a clear dominant pattern of inheritance and even 1 percent of “sporadic” cases. The arguments for G2019S being a pathogenic mutation are simple. Firstly, these groups have collectively sequenced hundreds of unaffected controls and have not found G2019S even once, arguing for a strong association with disease. Secondly, the study by Bonifati and colleagues shows convincing segregation. However, there is apparently incomplete penetrance of the phenotype as there are a couple of cases above the average age of onset that are not yet clinically affected. Presumably, the reports of mutations in apparently sporadic cases without reported family history reflect either people with de novo mutations or are due to affected cases with an affected parent who did not manifest disease. It is feasible that these individuals have a subclinical involvement, if we remember that it is estimated that 80 percent of striatal dopamine is lost before the onset of symptoms in PD. Therefore, the balance of evidence is that G2019S is real, is common, and might contribute significantly to the population risk for PD whether cases have been described as inherited or not.
What isn’t evidence for G2019S being pathogenic is that it is a conserved residue across species and across other kinases, although this happens to be true. The mutation site is part of a critical motif that binds the divalent metal cation important in the kinase activity (DYG in dardarin), and next to the I2020T mutation described by Zimprich and colleagues. The fact that G2019 is conserved tells us that it’s likely to be important in kinase activity, but we should have already figured this out, as the glycine is part of the motif that defines the known kinase family. What will be interesting to find out is if the kinase activity is required for pathogenic effects of dardarin mutations. There are hints from this work that the kinase domain is a hotspot for mutations, but not all mutations are in this exact region of the protein, leaving the contribution of the kinase activity an open question.
What a stunning turnaround in a field wherein people thought as late as 1997, and some even thereafter, that genetics were irrelevant to PD and it was all about environment! In the light of the MPTP story, obviously also an important advance, the field latched onto environmental factors so tenaciously that it lost sight of other key avenues to understanding the PD phenotype. Now, that neglect is being massively corrected, leading to better clinical tests, animal models, drug discovery efforts, etc. This field is hopping and we now know how naive our views of PD were just eight years ago. The lid has been blown off old concepts of PD as a group of diseases caused by multiple etiologies and pathologies with the only common thread being damage to the nigrostriatal pathway that is reflected in a movement disorder. Clearly, even that is not all Parkinson diseases encompasses, because dementia, too, is now recognized as a very big part of the phenotype.
The most important message for me here is the implication from these studies that genetic testing in PD patients should be more broadly directed, even to individuals without a family history of PD.
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