The G2019S LRRK2 mutation is uncommon amongst Greek patients with sporadic Parkinson's disease

The G2019S LRRK2 mutation is uncommon amongst Greek patients with sporadic Parkinson's disease
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  The G2019S LRRK2 mutation is uncommon amongst Greek patientswith sporadic Parkinson’s disease K. Kalinderi a , L. Fidani a , S. Bostantjopoulou b , Z. Katsarou b and A. Kotsis a a Department of General Biology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece; and   b Third Department of Neurology, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Keywords: G2019S mutation,LRRK2 gene, sporadicParkinson’s disease Received 3 January 2007Accepted 30 April 2007 Parkinson’s disease (PD) is the second most common neurodegenerative disorderaffecting approximately 2% of the population >60 years of age. Although, the eti-ology of PD is still unknown, the genetic background of the disease has been docu-mented. Recently, a mutation in the LRRK2 gene, G2019S, was associated with 3– 41% and 1–2% of familial and sporadic PD, respectively suggesting a pivotal role of LRRK2 in PD. In this report, we examine the association of the G2019S mutationwith sporadic late-onset PD, in an independent cohort of Greek patients and controls. Introduction Parkinson’s disease (PD) is a heterogeneous movementdisorder characterized by the progressive degenerationof dopaminergic neurons within the substantia nigra.There is considerable variation with respect to per-centage of people affected worldwide, with estimates of prevalence ranging from 65.6 to 12 500 per 100 000 andannual incidence rates from 5 to 346 per 100 000 [1].Incidence rates increase with age and men appear to beaffected more frequently than women [2]. PD is mainlyconsidered to be a sporadic disease, but various her-editary forms of parkinsonism have been recognized aswell. In fact, approximately 90–95% of the patientshave sporadic disease and 5–10% of PD cases arefamilial. Until now, the exact pathologic mechanism of the disease remains unknown.In the race of finding the genetic key component of PD, mutations in a recently identified gene called leu-cine-rich repeat kinase 2 (LRRK2) came along as amajor breakthrough. The LRRK2 gene was srcinallymapped in the PARK8 region located on chromosome12p11.2-q13, in a large Japanese family with autosomaldominant late-onset PD [3]. Today, more than 20LRRK2 mutations have been linked to autosomal-dominant parkinsonism, accounting for 6–7% of familial PD and for a significant fraction of sporadicPD cases [4]. Amongst the several pathogenic mutationsin this gene, the G2019S amino acid substitution, ini-tially identified by Paisan-Ruiz  et al.  [5] and Kachergus et al.  [6], is the most prevalent, detected in 3–41% of patients with familial PD and up to 1–2% of sporadiccases [5–31].To determine the prevalence of the G1019S mutationin our Greek population, we conducted genetic analysisof this mutation in 180 sporadic PD patients and 160control individuals. Patients and methods All patients were diagnosed according to UK Parkin-son’s Disease Society Brain Bank Clinical DiagnosticCriteria [32], in Papanikolaou Hospital, Thessaloniki,Greece. The control group consisted of individualswithout any symptoms of neurodegenerative disease.All PD and control individuals were ethnic Greek res-idents of northern Greece. The average age of the PDpatients screened for the G2019S LRRK2 mutation(115 males, 65 females) was 61.3 years (range: 52– 85 years); their average age at disease onset, 52.5 years(range: 50–72 years). The clinical phenotype was that of typical late onset sporadic PD. Additional relatives of the PD patients were either not available for study ordenied genotyping, as to positively exclude familial PD;however, the patients   family history provided no evi-dence to the contrary. The average age of controlindividuals (80 males, 80 females) recruited in this studywas 71.1 years (range: 62–86 years). The study wasapproved by the Aristotle University Medical SchoolBioethics Committee and informed consent was givenby all participants.Genomic DNA was extracted in all subjects fromperipheral blood leukocytes according to standardprocedures. The relevant portion in the exon 41 of theLRRK2 gene was amplified using the PCR method.The PCR conditions were optimized as follow: 94  C for5 min followed by 24 cycles of 94  C for 30 s, 60–50   Ctouchdown annealing for 30 s at 0.5  C per cycle, and72  C for 45 s, with a final extension at 72  C for 10 min.Subsequently, the genotyping for the G2019S mutationwas accomplished with the restriction fragment length Correspondence: Dr. Liana Fidani, Department of General Biology,Medical School, Aristotle University of Thessaloniki, Thessaloniki,Greece (tel.: +302310999165; fax: +302310999019;e-mail: 1088    2007 EFNS European Journal of Neurology   2007,  14:  1088–1090 doi:10.1111/j.1468-1331.2007.01867.x  polymorphism method. Digestion with  Sfc I restrictionenzyme (New England Biolabs Inc., Ipswich, MA,USA) at 37  C yields a 228 and a 109 bp band for thecommon G allele and a 207, 109 and 21 bp for the rareA allele respectively. Thereafter, digestion productswere resolved on a 3.5% agarose gel, stained in ethi-dium bromide solution and visualized with an ultravi-olet light. Positive control DNA, harboring the rare Aallele as to assess electrophoretic mobility differencesfollowing  Sfc I digestion compared with the common Gallele, was kindly provided by Dr. Coro Paisan-Ruiz(Laboratory of Neurogenetics, National Institute onAging, NIH, Bethesda, MD, USA). Results and discussion None of the 180 Greek sporadic PD patients tested inthis study displayed the LRRK2 G2019S substitution,despite it being the most commonly reported mutationin PD, so far. Although a definite conclusion cannot bedrawn due to the relatively small sample size as well asthe regional clustering (northern Greece) of the partic-ipants, our results seem to indicate that the G2019SLRRK2 mutation is not a major cause of PD in theGreek population. Indeed, a similar genetic study in PDpatients from the island of Crete (southern Greece) didnot detect the G2019S mutation in any of 174 sporadicPD patients examined [16], whereas in a yet differentstudy concerning Greek PD patients from the region of Thessaly (central Greece) [17], a single G2019Sheterozygote was found in a total of 235 sporadic cases(overall prevalence  ¼  0.17%). Genetic risk factorsmight be population specific and, therefore, it is notaltogether surprising that evidence for the commonG2019S LRRK2 mutation in sporadic PD was hardlyfound in Greece, even though such a low prevalencewas hitherto confined to Asian PD patients (0–0.34%)[18–22]. European PD patients outside the IberianPeninsula generally display higher frequencies (0.3– 1.4%) [4,12–15,23–28], as do US patients (0.37–0.7%)[29–31], whilst the mutation appears to be truly com-mon amongst the Spaniards and the Portuguese (2.7– 6.1%) [9–11]. Extreme values have been reported forNorth African Arabs (41%) [7] and Ashkenazi Jews (9– 18%) [8,31] but these refer mainly to familial cases. So,whether the G2019S LRRK2 mutation is more com-mon or specific to some races remains under investi-gation and the real prevalence of LRRK2 mutations indifferent ethnic groups needs to be confirmed in addi-tional cohorts.Whilst the importance of known LRRK2 mutations,including G2019S, in the context of PD pathogenesiscannot be denied, their low prevalence in most popu-lations examined so far, leaves the majority of PD casesunaccounted for, from a genetic point of view. Themagnitude of the G2019S mutation and in general of the LRRK2 gene would remain vague as long as therole of the encoded LRRK2 protein (dardarin) is notfigured out and the pathologic characteristics of themutated PD patients do not become more specific.Hitherto, the phenotype associated with LRRK2mutations is broad, with age of disease onset rangingfrom   30 to   80 years and with various degree of pathological heterogeneity. In addition, in some cases,Lewy bodies are absent, and unusual inclusions orpathological findings usually associated with differentneurodegenerative diseases are present [33].Another issue worth addressing in future studies isthat of penetrance. It has been reported that the pene-trance of the G2019S mutation increases in a quasilin-ear fashion, from 17% at  50 years old to 85% at agesover 70 years [6]. Whilst the low prevalence of G2019Smakes it inherently difficult to confirm this result insporadic PD, both phenotypic heterogeneity and vari-able penetrance could conceivably be explained if theeffect of the mutated dardarin turned out to be modifiedby prolonged exposure to environmental factors andfurther enhanced as a result of the age-related decline of endogenous defense systems [34].Future insights into the biological role of LRRK2and its possible interaction with other components of signal transduction pathways will undoubtedly providenew candidate genes for PD. In the meantime, the lowprevalence of LRRK2 G2019S in most populations, itsvariable penetrance and the heterogeneity of associatedphenotypes argue against its general use for diagnostic,prognostic or genetic counseling purposes, for the timebeing. Acknowledgements This work was supported in part by grant 81599 of theAristotle University Research committee. We thank Dr.Antonis Goulas for useful suggestions during prepar-ation of this manuscript; Dr. Coro Paisan-Ruiz forproviding the LRRK2 G2019S positive control DNA. References 1. von Campenhausen S, Bornschein B, Wick R,  et al. Prevalence and incidence of Parkinson’s disease inEurope.  European Neuropsychopharmacology  2005;  15: 473–490.2. Benito-Leon J, Bermejo-Pareja F, Morales-Gonzalez JM, et al.  Incidence of Parkinson disease and parkinsonism inthree elderly populations of central Spain.  Neurology 2004;  62:  734–741.3. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S,Obata F. A new locus for Parkinson’s disease (PARK8) Greek patients with sporadic PD  1089   2007 EFNS  European Journal of Neurology   14 , 1088–1090  maps to chromosome 12p11.2-q13.1.  Annals of Neurology 2002;  51:  296–301.4. Berg D, Schweitzer K, Leitner P,  et al.  Type and fre-quency of mutations in the LRRK2 gene in familial andsporadic Parkinson’s disease.  Brain  2005;  128:  3000–3011.5. 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