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
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