Letters to the Editor Related to Published Articles

GIGYF2 Variants Are Not Associated with

Parkinson’s Disease in Italy

We read with great interest the letter by Vilarino-Guellet al. on the prevalence of eight distinct variants of theGIGYF2 gene [MIM*612003] in two large series of Parkin-son’s disease (PD) patients and controls from North Americaand Norway.1 The authors studied seven possibly pathogenicvariants (p.N56S, p.T112A, p.I278V, p.S335T, p.N457T,p.D606E, p.V1242I) first described in French and Italian fam-ilial PD cases with an overall frequency of 4 and 5.7%respectively, as well as the p.H1171R variant, previouslydetected in one Italian control (0.8%).2 Among the cohortsscreened by Vilarino-Guell et al., only two variants werefound at very low frequency: p.N56S (0.7% Americanpatients) and p.H1171R (0.2–0.4% patients and 0.5–0.9%controls in the two groups).

Given the discrepancy between the two studies and thehigh frequency of GIGYF2 variants reported in Italianpatients with PD, we sought to assess whether this findingcould be replicated in a different Italian cohort. After obtain-ing written informed consent, we performed a mutationscreening of the whole GIGYF2 gene in 144 Italian PDpatients recruited at the Movement Disorders Clinic, CatholicUniversity of Rome. Mean age at time of study was 66.7 612.4 years (range, 24–98), mean age at onset 55.3 6 11.2years (range, 19–77), mean Hoehn and Yahr score 2.3 6 0.7(range, 1–5). Ninety-two (64%) patients had at least one first-degree affected relative (either one parent, 42%, or sibling,22%) whereas the remaining 52 (36%) were sporadic. Fur-thermore, we searched for the eight above-mentioned variantsin 180 unrelated controls from the same population (meanage, 68.6 6 10.1 years; range, 44–91). These were free ofneurological symptoms and with negative family history formovement disorders. The 27 coding exons and exon–intronjunctions of the GIGYF2 gene were PCR-amplified fromgenomic DNA and analyzed using denaturing high-perform-ance liquid chromatography (primers and conditions availableupon request). All samples with abnormal elution profileswere sequenced in both directions using standard procedures.

In our PD cohort, we did not identify possibly pathogenicvariants. Moreover, the eight variants tested by Vilarino-Guell et al. were not found either in patients or controls. Wedetected two heterozygous variants previously considerednonpathogenic (p.A572A in 2 patients andp.delLPQQQQQQ1209-1216 in one),2 and 15 polymorphismsalready annotated in dbSNP (rs11555646, rs2289913,rs2289912, rs34424361, rs2305139, rs1078323, rs3816334,rs1947105, rs7563724, rs12328151, rs60774345 rs1947105,

rs60774345, rs6437074, and rs10555297, with heterozygousfrequencies of 2.7–49.2%). Finally, a novel heterozygouschange in intron 5 (c.491112T>C) was detected in 2 patientsand one control.

Our data are in line with the results reported by Vilarino-Guell et al., and support their conclusion against a pathogenicrole for the eight originally described GIGYF2 variants.These findings are also substantiated by two recent largescreenings, one testing the entire gene in Portuguese andNorth American subjects, the other focused on analysis ofp.N56S and p.N457T variants in German and Austrianpatients.3,4 Overall, these eight variants have been tested inmore than 2,200 patients and 2,300 controls (Table 1). Var-iants p.N457T and p.H1171R occurred with similar frequencyin patients and controls, and are unlikely to be pathogenic.Five variants (p.T112A, p.I278V, p.S335T, p.D606E, andp.V1242I) were found only in isolated patients from the orig-inal study,2 and all were predicted as benign using PolyPhen(http://genetics.bwh.harvard.edu/pph/), a software estimatingthe possible impact of missense variants on a protein’s struc-ture and function. An increased frequency in patients com-pared with controls (P 5 0.01 at Fisher’s exact test) wasfound only for p.N56S, a variant predicted as ‘‘possibly dam-aging’’ by PolyPhen. However, segregation of this variantwith the disease was excluded in a familial case,4 and itspathogenic role in PD remains to be elucidated.

Our findings do not substantiate the previously reported5.7% frequency of GIGYF2 mutations in Italian PD patients.2

In their screening, Bras et al. reported other rare missensechanges, but none of these was significantly enriched in PDcases compared with controls.3 These results are also in linewith published studies that, using either haplotype tagging orgenome-wide approaches, failed to detect any significantassociation between GIGYF2 polymorphisms and PD risk.5–7

Overall, currently available data argue against a major rolefor GIGYF2 in PD. The pathogenicity of the identified rare var-iants remains uncertain, and needs to be addressed by investi-gating the impact of such variants on the protein function.

Acknowledgments: This work was supported with grantsfrom Telethon Foundation (GGP07210 to EMV) and ItalianMinistry of Health (Ricerca Corrente 2009, Ricerca Finaliz-zata ex. articolo 56, Progetto Ordinario Ricerca Finalizzata toBD and ARB). The support of Fondazione Livio Patrizi andTransgenomics is also gratefully acknowledged. EMV hadfull access to all of the data in the study and takes responsi-bility for the integrity of the data and the accuracy of thedata analysis.

Author roles: Monica Bonetti and Alessandro Ferraris,execution of the project, data and statistical analysis, manu-script writing; Martina Petracca and Anna Rita Bentivoglio,ascertainment of patients, data analysis; Bruno Dallapiccolaand Enza Maria Valente, design of the study and critical re-vision of the manuscript for intellectual content.

Published online 26 June 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22640

1867

Movement DisordersVol. 24, No. 12, 2009, pp. 1867–1869� 2009 Movement Disorder Society

Monica Bonetti, BScAlessandro Ferraris, MD

CSS-Mendel InstituteIRCCS Casa Sollievo della Sofferenza Hospital

Rome, Italy

Martina Petracca, MDAnna Rita Bentivoglio, MD, PhD

Institute of NeurologyCatholic University

Rome, Italy

Bruno Dallapiccola, MDCSS-Mendel Institute

IRCCS Casa Sollievo della Sofferenza HospitalRome, Italy

Enza Maria Valente, MD, PhD*CSS-Mendel Institute

IRCCS Casa Sollievo della Sofferenza HospitalRome, Italy

Department of Medical and SurgicalPediatric Sciences

University of MessinaMessina, Italy

*E-mail: e.valente@css-mendel.it

References

1. Vilarino-Guell C, Ross OA, Soto AI, et al. Reported mutations inGIGYF2 are not a common cause of Parkinson’s disease. MovDisord 2009;24:618–619.

2. Lautier C, Goldwurm S, Durr A, et al. Mutations in the GIGYF2(TNRC15) gene at the PARK11 locus in familial Parkinson dis-ease. Am J Hum Genet 2008;82:822–833.

3. Bras J, Simon-Sanchez J, Federoff M, et al. Lack of replication ofassociation between GIGYF2 variants and Parkinson disease. HumMol Genet 2009;18:341–346.

4. Zimprich A, Schulte C, Reinthaler E, et al. PARK11 gene(GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenicfor Parkinson’s disease. Parkinsonism Relat Disord 2009 [Epubahead of print].

5. Sutherland GT, Siebert GA, Newman JR, et al. Haplotype analysisof the PARK 11 gene, GIGYF2, in sporadic Parkinson’s disease.Mov Disord 2008;24:448–452.

6. Fung HC, Scholz S, Matarin M, et al. Genome-wide genotypingin Parkinson’s disease and neurologically normal controls: firststage analysis and public release of data. Lancet Neurol 2006;5:911–916.

7. Maraganore DM, de AM, Lesnick TG, et al. High-resolutionwhole-genome association study of Parkinson disease. Am J HumGenet 2005;77:685–693.

Reply: GIGYF2 Variants Are Not Associated

With Parkinson’s Disease in Italy

We welcome the study of Bonetti and colleagues examiningthe role of GIGYF2 variants in an Italian population withParkinson’s disease (PD). The GIGYF2 was nominated as thegene responsible for PARK11 linkage by Lautier and col-leagues. Since this report, several studies have not found anyevidence to support these findings. Bonetti and colleagueshave now confirmed this lack of replication in a PD series ofsamples ethnically-matched to one population used in theoriginal study. In addition, Nichols et al.1 have recently ruledout GIGYF2 mutations in families linked to PARK11. Taken

TABLE 1. Frequency of eight GIGYF2 variants in PD patients and controls in literature

Reference Country Subjects Number

c.167A>G c.334A>G c.832A>G c.1003T>A c.1370A>C c.1818C>G c.3724G>A c.3512A>G

p.N56S p.T112A p.I278V p.S335T p.N457T p.D606E p.V1242I p.H1171R

2 France pts 126 3 (2.38) 0 0 0 1 (0.79) 1 (0.79) 0 0ctr 96 0 0 0 0 0 0 0 0

2 Italy pts 123 1 (0.81) 1 (0.81) 1 (0.81) 1 (0.81) 2 (1.62) 0 1 (0.81) 0ctr 131 0 0 0 0 0 0 0 1 (0.76)

1 Norway pts 696 0 0 0 0 0 0 0 3 (0.43)ctr 614 0 0 0 0 0 0 0 3 (0.48)

1 USA pts 443 3 (0.67) 0 0 0 0 0 0 1 (0.22)ctr 427 0 0 0 0 0 0 0 4 (0.93)

3 Portugal pts 267 0 0 0 0 0 0 0 0ctr 451 0 0 0 0 1 (0.22) 0 0 0

3 USA pts 460 0 0 0 0 0 0 0 4 (0.86)ctr 460 0 0 0 0 0 0 0 1 (0.21)

4 Germany-Austria

pts 669 1 (0.14) nt nt nt 1 (0.14) nt nt ntctr 1051 1 (0.09) nt nt nt 3 (0.28) nt nt nt

Present Italy pts 144 0 0 0 0 0 0 0 0ctr 180 0 0 0 0 0 0 0 0

Total pts 2259/2928a 8 (0.27)a 1 (0.04) 1 (0.04) 1 (0.04) 4 (0.14)a 1 (0.04) 1 (0.04) 9 (0.40)ctr 2359/3410a 1 (0.03)a 0 0 0 4 (0.12)a 0 0 8 (0.34)

Variants are described at the genomic level (upper line) and at the protein level (lower line). Percentage values are in brackets.pts, patients; ctr, controls; nt, not tested.aFigures calculated including the article by Zimprich et al. (only two variants tested).

Published online 9 June 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.22614

1868 LETTERS TO THE EDITOR

Movement Disorders, Vol. 24, No. 12, 2009

together, these data strongly suggest that GIGYF2 is neitherresponsible for PARK11 nor a gene implicated in PD.

When a novel genetic cause of PD is nominated evidenceof pathogenicity is crucial. This evidence comes from segre-gation in large multi-incident families or consistent signifi-cant association with disease in multiple independent sampleseries. Unfortunately, the initial study of Lautier et al. lackedboth, and this has resulted in the failed replication efforts.Genetic studies drive functional biology, and the generationof new disease model systems, which places a burden ofresponsibility on the geneticist to prove beyond reasonabledoubt the authenticity of each nominated PD locus.

Carles Vilarino-Guell, PhD*

Owen A. Ross, PhD

Matthew J. Farrer, PhDDivision of Neurogenetics

Department of NeuroscienceMayo ClinicJacksonville

Florida*E-mail: vilarinoguell.carles@mayo.edu

References

1. Nichols WC, Kissell DK, Pankratz N, Pauciulo MW, ElsaesserVE, Clark KA, Halter CA, Rudolph A, Wojcieszek J, Pfeiffer RF,Foroud T, for the Parkinson Study Group–PROGENI Investiga-tors. Variation in GIGYF2 is not associated with Parkinson dis-ease. Neurology 2009 (Epub ahead of print).

Movement Disorders, Vol. 24, No. 12, 2009

1869LETTERS TO THE EDITOR