Variation in GIGYF2 is not associated with Parkinson disease

Abstract

Objective: A recent study reported that mutations in a gene on chromosome 2q36-37, GIGYF2, result in Parkinson disease (PD). We have previously reported linkage to this chromosomal region in a sample of multiplex PD families, with the strongest evidence of linkage obtained using the subset of the sample having the strongest family history of disease and meeting the strictest diagnostic criteria. We have tested whether mutations in GIGYF2 may account for the previously observed linkage finding.

Methods: We sequenced the GIGYF2 coding region in 96 unrelated patients with PD used in our original study that contributed to the chromosome 2q36-37 linkage signal. Subsequently, we genotyped the entire sample of 566 multiplex PD kindreds as well as 1,447 controls to test whether variants in GIGYF2 are causative or increase susceptibility for PD.

Results: We detected three novel variants as well as one of the previously reported seven variants in a total of five multiple PD families; however, there was no consistent evidence that these variants segregated with PD in these families. We also did not find a significant increase in risk for PD among those inheriting variants in GIGYF2 (p = 0.28).

Conclusions: We believe that variation in a gene other than GIGYF2 accounts for the previously reported linkage finding on chromosome 2q36-37.

Figure 1 Segregation of GIGYF2 variants in pedigrees The GIGYF2 variant identified in each family is indicated above the pedigree. To maintain the anonymity of the pedigree, the gender of all subjects is denoted as female. PD = Parkinson disease.

Figure 2 Schematic of GIGYF2 gene (A) and amino acid/DNA sequence of GIGYF2 polymorphic exon 25 alleles (B) (A) Schematic of GIGYF2 gene showing location of identified variants. The GIGYF2 gene structure is depicted approximately to scale with the exons numbered above the gene. Below the gene are shown variants identified in patients with PD. Those in boxes represent the three novel variants of this report while the remaining seven were previously published. (B) Amino acid/DNA sequence of GIGYF2 polymorphic exon 25 alleles. At top is shown the amino acid sequence corresponding to the 3′ portion of exon 25 encoding residues 1200 to 1228 (numbers above amino acid sequence). Shown directly below the amino acid sequence are the eight different alleles identified in our study sample. Numbers at left designate allele sizes (bp) by fluorescent genotyping. The 160 bp allele is the normal reference allele based on the GenBank sequence. All other alleles are shown relative to the normal 160 bp allele. Missing residues are depicted as underlined gaps in the sequence. The QQ insertion at residue 1217 in allele 163 is indicated by the underlined CAG codons occurring between codons 1216 and 1217 in the normal sequence.