Not Just a Family Affair: Dardarin Mutations Predict Sporadic PD
In last October’s Neuron, Paisan-Ruiz et al. and Zimprich et al. revealed that the gene LRRK2, encoding a protein kinase dubbed “dardarin” (from the Basque for tremor), is one and the same with PARK8, a locus on chromosome 12 that is strongly associated with Parkinson disease (PD) (see ARF related news story). Those papers revealed several dardarin missense mutations that co-segregate with affected family members in Spain, North America, and England. Now, three papers published online this week in Lancet reveal yet another dardarin mutation. This one may be particularly interesting because it is found not only in a large proportion of familial PD cases, but also in a number of non-familial, or idiopathic, cases, as well.
In one paper, Vincenzo Bonifati, at the Erasmus Medical Center, Rotterdam, together with colleagues there and from the Italian Parkinson Genetics Network, report on their search for novel dardarin mutations in 61 families affected by PD (51 Italian, nine Brazilian and one from Portugal). First author Alessio DiFonzo and colleagues found that one missense mutation, which results in the replacement of a glycine with a serine at position 2019 of the protein, was responsible for PD in 16 patients from four unrelated families.
William Nichols and colleagues, at Cincinnati Children’s Hospital and from the Parkinson Study Group-PROGENI, found a similar incidence of this same mutation North America. It appeared in 20 families out of 358 tested, or five percent. The same percentage of individual carriers was also found on testing 767 patients. “No other single mutation identified so far in this or any other gene associated with Parkinson disease has occurred with such high frequency in familial or sporadic patients,” write the authors. Consequently, screening for this mutation may become a diagnostic tool, both for people who already have symptoms and for those who may be at risk for developing this disease.
The G2019S mutation lies smack in the middle of a highly conserved motif found in the catalytic domain of all human kinases. But what is surprising about this mutation is that although it is autosomal-dominant, disease onset varies considerably with age, as is also true for presenilin mutations causing Alzheimer’s. Bonifati’s group present clinical data for 10 of the 16 affected patients showing that age of onset ranged from 38 to 68 years. The data suggest that there are other factors mitigating progression of PD caused by this mutation (see also comment below by Mark Cookson).
Perhaps even more remarkable is the third paper by Nicholas Wood and his colleagues at the Institute of Neurology, London. Together with Bonifati and Andrew Singleton and colleagues at the National Institute on Aging in Bethesda, Maryland, first author William Gilks reveals that the same mutation is found in non-familial PD. Of 482 patients that had been classed as having this idiopathic form of the disease, Wood found eight had the G2019S mutation. Three of these patients turned out to have first-degree relatives with the disease, suggesting that these were really familial cases to begin with. But in five patients, no family history could be ascertained. Again, this result suggests that the mutation is not fully “penetrant,” i.e., it may not always cause the disease, and that these five patients have immediate ancestors who are carrying the mutation but never developed PD. This raises the question of how many asymptomatic carriers live in the general population? This may be pretty rare because in DNA samples from 345 controls, Gilks and colleagues did not find one dardarin mutation. An alternative explanation for the five cases is that the mutation arose afresh in these individuals.
In an accompanying comment, Alexis Brice at INSERM in Paris, France, raises the issue of gene copy number toward reconciling some of the data. Possibly, differences in the number of LRRK2 copies in the genome of patients could explain the apparent difference in penetrance. This could have important clinical implications. “Because accurate evaluation of risk associated with the mutation is crucial for appropriate genetic counseling, copy number is also an important issue,” the author writes.—Tom Fagan
- Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005 Apr;76(4):672-80. PubMed.
- Di Fonzo A, Rohé CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V, . A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):412-5. PubMed.
- Nichols WC, Pankratz N, Hernandez D, Paisán-Ruíz C, Jain S, Halter CA, Michaels VE, Reed T, Rudolph A, Shults CW, Singleton A, Foroud T, . Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):410-2. PubMed.
- 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. PubMed.
- Brice A. How much does dardarin contribute to Parkinson's disease?. Lancet. 2005 Jan 29-Feb 4;365(9457):363-4. PubMed.
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National Institute on Aging
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.
University of Pennsylvania
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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