Variation in GIGYF2 is not associated with Parkinson disease

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Neurology (Impact Factor: 8.29). 04/2009; 72(22):1886-92. DOI: 10.1212/01.wnl.0000346517.98982.1b
Source: PubMed


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

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Available from: Veronika E Elsaesser, Oct 24, 2014
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    • "Sequence analysis of the gene (Lautier et al., 2008) revealed 7 different genetic variants in 12 of 249 unrelated familial PD patients from Italy and France; the same mutations were absent in 227 controls. Although GIGYF2 represents a good candidate for PD, given its potential involvement in insulin and insulin-like growth factor (IGF) signaling (Dufresne and Smith, 2005), several further studies did not confirm its association with PD (Bras et al., 2009; Di Fonzo et al., 2009; Guo et al., 2009; Meeus et al., 2009; Nichols et al., 2009; Sutherland et al., 2009; Tan et al., 2009; Vilariño-Güell et al., 2009; Zimprich et al., 2009). Moreover, a functional validation of GIGYF2 mutations is still lacking, mainly because of the toxicity of the recombinant protein in eukaryotic cells (Giovannone et al., 2003), and the gene function is unknown. "
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    ABSTRACT: The Grb10-Interacting GYF Protein-2 (GIGYF2) gene has been proposed as the Parkinson-disease (PD) gene underlying the PARK11 locus. However, association of GIGYF2 with PD has been challenged and a functional validation of GIGYF2 mutations is lacking. In this frame, we performed a mutational screening of GIGYF2 in an Italian PD cohort. Exons containing known mutations were analyzed in 552 cases and 552 controls. Thereafter, a subset of 184 familial PD cases and controls were subjected to a full coding-exon screening. These analyses identified 8 missense variations in 9 individuals (4 cases, 5 controls). Furthermore, we developed a zebrafish model of gigyf2 deficiency. Abrogation of gigyf2 function in zebrafish embryos did not lead to a drastic cell loss in diencephalic dopaminergic (DA) neuron clusters, suggesting that gigyf2 is not required for DA neuron differentiation. Notably, gigyf2 functional abrogation did not increase diencephalic DA neurons susceptibility to the PD-inducing drug MPP+. These data, together with those recently reported by other groups, suggest that GIGYF2 is unlikely to be the PARK11 gene.
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    • "GIGYF2 encodes a component of the insulin-signaling pathway and is expressed in the brain.129 However, replication studies have failed to demonstrate the pathogenicity of these mutations,130,131 and the original PARK11 family used to define the locus has no mutation in GIGYF2.132 Therefore, it seems unlikely that GIGYF2 plays a role in susceptibility to Parkinson’s disease. "
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    • "Indeed, the Asn457Thr and His1171Arg mutations were also found in controls, suggesting a minor role for GIGYF2 in PD development. Furthermore, accumulating evidence shows that GIGYF2 does not associate with PD, suggesting that GIGYF2 may not be the causative PD gene in the PARK11 locus (Nichols et al., 2009; Sutherland et al., 2009; Meeus et al., in press; Zimprich et al., in press). "
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