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ARTICLES: W. C. Nichols, V. E. Elsaesser, N. Pankratz, M. W. Pauciulo, D. K. Marek, C. A. Halter, A. Rudolph, C. W. Shults, T. Foroud For the Parkinson Study Group– PROGENI Investigators LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8 Neurology 2007; 69: 1737-1744 [Abstract] [Full text] [PDF]

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LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8

Vincenzo Bonifati, Yah-Huei Wu-Chou, Dorothea Schweiger, Alessio Di Fonzo, Chin-Song Lu, and Ben Oostra. Rotterdam, The Netherlands and Taoyuan, Taiwan   (27 December 2007)

Reply from the authors

William C. Nichols, Veronika E. Elsaesser, Nathan Pankratz, Michael W. Pauciulo, Diane K. Marek, Cheryl A. Halter, Alice Rudolph, Tatiata Foroud   (27 December 2007)

LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8 27 December 2007
Vincenzo Bonifati, Dept. Clinical Genetics, Erasmus MC Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands, Yah-Huei Wu-Chou, Dorothea Schweiger, Alessio Di Fonzo, Chin-Song Lu, and Ben Oostra. Rotterdam, The Netherlands and Taoyuan, Taiwan Send Correspondence to journal: Re: LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8 v.bonifati{at}erasmusmc.nl Vincenzo Bonifati, et al.	Nichols et al. report novel sequence variants in the LRRK2 gene detected in patients with Parkinson’s disease (PD), and they highlight that additional data are required to determine whether these variants represent pathogenic mutations or rare neutral variants. [1] An accurate evaluation of pathogenicity of novel variants identified in patients is crucial not only to build hypotheses about disease mechanisms but also to assist counseling of patients. In the Introduction, Nichols et al. state that, “Although rare in most populations, the R1441G and G2385R mutations are found at higher rates in the Basque region of Spain and the Han Chinese, respectively”. We originally reported that the G2385R variant is a polymorphism, present in heterozygous state in ~5% of the Han Chinese population in Taiwan, but it is significantly more common in sporadic PD from that population. [2] We proposed the G2385R variant as a risk factor for PD. This association was since replicated in different large samples from the Chinese and Japanese populations (cumulative odd ratio ~2, reviewed in [3]). Thus, G2385R might represent an important genetic risk factor for PD, but it should not be referred to as a “mutation”, nor be considered like other, highly-penetrant “PD-causing” LRRK2 mutations. Furthermore, Nichols et al. state that to date, no nonsense/frameshift mutations have been reported in the LRRK2 gene in association with PD, elaborating further on the implications of this assumption for the mechanisms of this disease. However, we previously reported a heterozygous LRRK2 nonsense variant (c.G5620T) in a Taiwanese patient with sporadic PD. The mutation is predicted to encode a truncated protein missing the entire kinase and WD domain, p.E1874X. Whether p.E1874X is a rare disease-unrelated variant or a pathogenic mutation remains unclear. We detected it in a sporadic PD case, and no relatives were available for testing. The p.E1874X substitution could be a disease-causing de novo mutation or an inherited mutation displaying reduced penetrance. Truncating mutations in LRRK2 have been described in association with PD. Interestingly, a recent study suggests that loss of LRRK2 function induces degeneration of dopaminergic neurons in Drosophila. [4] We believe that further investigation is necessary to characterize the LRRK2 mutational spectrum and understand whether LRRK2 mutations cause PD by gain- or loss-of-function. References 1. Nichols WC, Elsaesser VE, Pankratz N, et al. LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology E-Pub ahead of print, Sep. 5 2007. 2. Di Fonzo A, Wu-Chou YH, Lu CS, et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 2006;7:133-138. 3. Bonifati V. LRRK2 Low-penetrance Mutations (Gly2019Ser) and Risk Alleles (Gly2385Arg)-Linking Familial and Sporadic Parkinson's Disease. Neurochem Res, 2007;32:1700-1708. 4. Lee SB, Kim W, Lee S, Chung J. Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun 2007;358:534-539. Disclosure: The authors report no conflicts of interest.
Reply from the authors 27 December 2007
William C. Nichols, Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue, 1469 TCHRF, Cincinnati OH 45140, Veronika E. Elsaesser, Nathan Pankratz, Michael W. Pauciulo, Diane K. Marek, Cheryl A. Halter, Alice Rudolph, Tatiata Foroud Send Correspondence to journal: Re: Reply from the authors bill.nichols{at}cchmc.org William C. Nichols, et al.	We appreciate the comments of Bonifati et al. concerning our recent article [1] and their important contributions to the field of PD genetics, especially in understanding the contributions of LRRK2 mutations/variants to disease pathogenesis. In an effort to adhere to length restrictions for the manuscript, we inadvertently used the term mutation when referring to both the R1441G substitution which is found in the Basque population and the G2385R substitution which, at the time of acceptance of our paper, had only been reported at a high frequency in the Taiwanese population with the allele frequency of 2.5% in controls and 5% in sporadic PD patients. [2] They are correct that based on the current data, the G2385R substitution is more appropriately termed a 'risk variant' and not a 'mutation'. Since the acceptance of our manuscript, Dr. Bonifati has published replication of PD association with this variant in different large samples from Chinese and Japanese populations. [3] In addition, we incorrectly stated in our manuscript that no LRRK2 truncating mutations had been reported in association with PD. Dr. Bonifati et al previously reported heterozygosity for a Q1874X variant in a single PD patient. As pointed out by them, “the identification of this allele could be a coincidental finding due to the large number of individuals sequenced” or it “could also represent a true disease-causing de novo mutation or an inherited mutation displaying reduced penetrance.” No other family members were available for study. To date, this remains the only report of a truncating LRRK2 mutation identified among the thousands of PD patients and controls who have been sequenced at the LRRK2 locus. Nonetheless, this identified change cannot be overlooked and if shown to be a disease-causing mutation would certainly necessitate alteration of the current hypothesis as to the mechanism by which LRRK2 mutations lead to PD. As pointed out by Bonifati et al, another paper which was just recently published, (after acceptance of our manuscript), suggests that loss of LRRK2 function induces degeneration of dopaminergic neurons in Drosophila. [4] As we stated and was echoed by Bonifati et al, we believe an accurate determination of the pathogenicity of newly identified LRRK2 variants is important not only for the counseling of patients and at risk individuals, but in helping to establish mechanisms whereby mutations/variants in LRRK2 can result in PD. Disclosure: The authors report no conflicts of interest.