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Clin Genet 2007: 71: 367370 Printed in Singapore.

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# 2007 The Authors Journal compilation # 2007 Blackwell Munksgaard

CLINICAL GENETICS doi: 10.1111/j.1399-0004.2007.00771.x

Letter to the Editor

LRRK2 G6055A mutation in Italian patients with familial or sporadic Parkinsons disease
To the Editor: Alterations in the leucine-rich kinase 2 gene (LRRK2; MIM *609007) have been shown to cause an autosomal dominant form of PARK8linked parkinsonism (1, 2). Within this gene, the G6055A mutation (exon 41; Gly2019Ser) represents the most common mutation described to date both in familial and in sporadic forms of Parkinsons disease (PD). To assess the G6055A mutation, we sequenced LRRK2 exon 41 of 488 unrelated patients with PD from southern Italy. Diagnosis of PD was based on the UK Brain Bank criteria. The Mini-Mental State Examination (MMSE) was used to assess cognitive conditions. The MMSE scores were adjusted for age and education. The mean age at disease onset was 59.3 10.4 years (range 3078). The average age at examination was 66.2 9.3 years (range 3188). Median HoehnYahr score was 2.5 (range 11.65) and median Unified Parkinsons Disease Rating Scale (UPDRS) score was 35 (range 7.5105). Moreover, we genotyped 180 unrelated healthy control subjects from the same geographical area, not including patients spouses, ageing 74.7 7.5 years, previously evaluated by a neurologist. All participants were recruited through the Institute of Neurology at the University of Magna Graecia of Catanzaro and all of them gave informed consent. At the time of recruitment of patients with PD, 38 of them were found to be suffering from autosomal dominant PD and 450 from sporadic PD. Subsequently, the LRRK2 G6055A mutation was tested in patients with PD and healthy controls. Moreover, the haplotype of the mutation carriers was constructed by typing 14 intragenic and flanking markers (Table 1). A telephone interview with the first degree relatives (37 subjects) of the G6055A mutation carriers (3) revealed that a brother (age 70 years) of the apparently sporadic patient AD3 was of healthy appearance at the time of the enrolment, developed PD later, and that the patients father, deceased at the age of 75, exhibited limb tremor and walking slowness during his last years. Therefore, we included this patient into the familial PD group. Among the 39 patients with familial PD, we identified three carriers (7.7%, 95% CI 2.6520.3) of G6055A mutation. Two of them were heterozygous and one was homozygous. The homozygous patient descends from a PD family with consanguineous mating and with deceased affected members in both maternal and paternal ascendants. A living sibling diagnosed with PD showed the same rare homozygous genotype. Among the 449 examined sporadic patients with PD, we found the heterozygous G6055A mutation in 11 subjects (2.5%, 95% CI 1.44.3) referring first-degree relatives free from neurological or psychiatric symptoms (except for a single subject suffering from depression). The mutation was absent in the control population. Any different mutation was found in the exon 41 of the examined patients with PD. Clinical features were similar between patients with PD with the mutation (Table 2) and the remaining patients with PD. Homozygous could not be distinguished from heterozygous carriers. The mean age at PD onset of mutation carriers is slightly younger (54.07 10.54) than in more common forms of the disease. A peculiar chromosome 12q12 haplotype, indicative of a common ancestor, is shared by the carriers of European and North African descent (4, 5), whereas some recently identified Japanese patients with PD showed a distinct haplotype (6, 7). In the present study, the haplotype was unambiguously determined for the single patient with PD homozygous for all the examined markers, including the G6055A mutation. Heterozygous carriers showed genotypes compatible with a common founder. The minimum shared haplotype, including $127 Kb region, spans from marker D12S2516 (intron 30) to D12S2519 (3# flanking). Concerning the D12S2515 microsatellite, we found two subclasses of patients with PD: the first group carrying at least one 226 bp allele, and the second patient with at least one 230 bp allele. It was hypothesized that a mutation occurring within this polymorphic marker could produce a subhaplotype in the contest of the ancestral haplotype extending beyond the
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Table 1. Haplotype analysis of the LRRK2 locus in G6055A mutation carriers Familial PD Marker D12S2514 D12S2515 D12S2516 rs1896252 rs1427263 rs11176013 rs11564148 G6055A D12S2518 D12S2519 D12S2520 D12S2521 D12S2522 D12S2523 D12S2517 Physical position 38874 38974 38989 39000 39000 39000 39000 39020 39034 39116 39120 39128 39132 39147 39282 K K K K K K K K K K K K K K K AD 1 290 226 256 C A G A A 153 132 259 362 299 318 193 AD 2 290 218/226 256 C A G A/T G/A 153 132/140 253/256 325/362 288/299 212/318 193/207 AD 3 290/293 214/226 256 C A G A G/A 153 132 259 362/374 299 318 187/193 Sporadic PD Case 1 290/293 226 256 C A G A G/A 153 132 256/259 362 299 318 193 Case 2 290 214/226 256 C/T A G/A A/T G/A 153 132/138 253/259 318/362 299/302 312/318 181/193 Case 3 290 230 256 C A G A G/A 153 132 256/259 362/370 299 318 183/193 Case 4 290/293 226/230 254/256 C/T A/C G/A A/T G/A 153 132/138 247/259 334/366 292/299 315/318 193 Case 5 290/293 218/226 256 C A G A/T G/A 153 132/134 256/259 362/382 299 303/318 191/193 Case 6 290 222/226 254/256 C/T A/C G/A A/T G/A 153 132/134 259 318/362 284/299 312/318 193/207 Case 7 290/293 222/230 254/256 C/T A/C G/A A/T G/A 153 132/134 253/259 362/370 299 303/318 187/193 Case 8 290 218/226 256 C A G A G/A 153 132/140 253/259 318/362 284/299 315/318 191/193 Case 10 290/296 210/226 256 C A G A/T G/A 153/169 132 250/259 362/374 299 318 185/193 Case 11 290 214/230 256 C A G A G/A 153 132/138 247/259 330/362 282/299 315/318 193/195 Case 12 290/293 230 254/256 C/T A/C G/A A/T G/A 153 132/140 256/259 318/362 284/299 312/318 193/205 Both alleles are shown when chromosomal phase could not be set (heterozygous subjects). The haplotype shared by G6055A carriers is highlighted in grey. Dark grey indicates the minimum shared region. K kilobases.

Letter to the Editor

Letter to the Editor


Table 2. Clinical summary of G6055A mutation carriers Cognitive function MMSE score Resting (adjusted for tremor, Age age and Disease HoehnYahr rigidity, L-dopa L-dopa at PD Initial complications off stage UPDRSb response education) Sex Age onset symptoms bradykinesia dose Autosomal dominant AD 1a F 62 AD1 siba M 68 AD 2 F 54 AD 3 M 68 Sporadic PD Case 1 F 58 Case 2 M 68 Case 3 F 61 Case 4 M 44 Case 5 F 72 Case 6 F 65 Case 7 F 70 Case 8 M 80 Case 10 M 41 Case 11 F 50 Case 12 M 61
a b

PD 53 49 49 62 46 57 53 42 67 57 54 77 39 41 60

Bra Tre Tre Bra Tre Tre/bra Bra Tre/bra Bra Tre Bra Tre Bra

All All All All All All All All All All All All Bra

750 1000 875 750 562.5 650 375 250 400 675 750 0 400

Good Good Good Good Good Good Good Good Good Good Good Good Good

28 27 26 23 25 26 16 30 18 23 20 26

n n d n n n d n d n n n

PDD/delay on 3 EMD 5 PDD 3 Absent 4 PDD/on off Alluc. PDD Absent Absent No on PDD/WO 4 3 2 1 2 4 5 2.5 1.5

43.5 67.5 39 52 65.5 72 22 9 42.5 69.5 77 35 19.5

28 n

Absent

Homozygous siblings. One of them was excluded from statistical analysis. Baseline condition. bra, bradykinesia; d, cognitive decline; EMD, early morning dystonia; n, normal; PDD, peak dose dyskinesia; tre, tremor; WO, wearing off; UPDRS, Unified Parkinsons Disease Rating Scale.

D12S2515 marker (8). A recombination event is also possible. The prevalence of the G6055A mutation appears to be related to ethnic factors and is population specific. The mutation is frequent in Caucasian (4), North African (9) and Ashkenazi Jews populations (10) but is rare in Asians (6). We found the frequency of familial carriers to be slightly higher compared to that reported in other Italian studies (8, 11). The G6055A mutation shows a reduced agerelated penetrance, increasing from 17% at 50 years of age to 85% at 70 years of age in a close to linear fashion (4). An incomplete penetrance might account for the presence of the mutation in asymptomatic family members reported elsewhere as well as in apparently sporadic patients with PD. The first direct evidence for a reduced penetrance was recently showed in a healthy octogenarian heterozygous carrier without family history of neurological disorders (12). The age-at-onset variability of mutation carriers suggests that other different environmental or genetic factors contribute to disease evolution. This variability is independent of APOE genotype and is not influenced by four common coding single nucleotide polymorphisms (SNPs) located in different functional domains of LRRK2 (13). Finally, since we sequenced the single exon 41, we were not able to exclude the presence of additional LRRK2 mutations in our patients with PD, hence

we may be underestimating the weight of this gene in our Italian population. D Civitellia P Tarantinoa G Nicolettia IC Ciro` Candianoa F Annesia EV De Marcoa S Carrideoa FE Roccaa F Condinoa P Spadaforaa P Puglieseb S DAserob M Morellib S Paglionicob G Annesia A Quattronea,b a Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy, and bInstitute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy
References
1. Paisan-Ruiz C, Jain S, Evans EW et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinsons disease. Neuron 2004: 44: 595600.

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Letter to the Editor


2. Zimprich A, Biskup S, Leitner P et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004: 44: 601607. 3. Kis B, Schrag A, Ben-Shlomo Y et al. Novel three-stage ascertainment method: prevalence of PD and parkinsonism in South Tyrol, Italy. Neurology 2002: 58: 18201825. 4. Kachergus J, Mata IF, Hulihan M et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005: 76: 672 680. 5. Lesage S, Leutenegger AL, Ibanez P et al. LRRK2 haplotype analyses in European and North African families with Parkinsons disease: a common founder for the Gly2019Ser mutation dating from the 13th century. Am J Hum Genet 2005: 77: 330332. 6. Tomiyama H, Li Y, Funayama M et al. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinsons disease patients from 18 countries. Mov Disord 2006: 21: 1102 1108. 7. Zabetian CP, Morino H, Ujike H et al. Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease. Neurology 2006: 67: 697 699. 8. Goldwurm S, Di Fonzo A, Simons EJ et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinsons disease and originates from a common ancestor. J Med Genet 2005: 42: e65. 9. Lesage S, Durr A, Tazir M et al. LRRK2 G2019S as a cause of Parkinsons disease in North African Arabs. N Engl J Med 2006: 354: 422423. 10. Ozelius LJ, Senthil G, Saunders-Pullman R et al. LRRK2 G2019S as a cause of Parkinsons disease in Ashkenazi Jews. N Engl J Med 2006: 354: 424425. 11. Marongiu R, Ghezzi D, Ialongo T et al. Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinsons disease. Mov Disord 2006: 21: 12321235. 12. Kay DM, Kramar P, Higgins D et al. Escaping Parkinsons disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005: 20: 1077 1078. 13. Paisan-Ruiz C, Lang AE, Kawarai T et al. LRRK2 gene in Parkinson disease: mutational analysis and case control association study. Neurology 2005: 65: 696700.
Correspondence: Professor Aldo Quattrone Istituto di Neurologia ` di Medicina Facolta Campus Universitario Germaneto 88100 Catanzaro Italy Tel.: 139-0961/3697011 Fax: 139-0961/3647177 e-mail: a.quattrone@isn.cnr.it

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