Lack of replication of association between GIGYF2 variants and Parkinson disease

Abstract

Mutations in GIGYF2 have recently been described as causative of Parkinson's disease in Europeans. In an attempt to replicate these results in independent populations, we sequenced the entire coding region of GIGYF2 in a large series of Portuguese and North American samples. We report the finding of two of the previously published mutations in neurologically normal Control individuals. This suggests that mutations in GIGYF2 are not strongly related to the development of the disease in either of these populations.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…A Belgian study found two heterozygous mutations in three sporadic PD cases (out of altogether 305 sporadic and familial cases), but the pathogenicity of these mutations was not clear [255]. Another study of North American and Portuguese PD cases found two of these mutations, but only in healthy persons [256], and a study of primarily Italian cases found no mutations [257], casting doubt whether the GIGYF2 is a causative PD gene. In a large sample of US and Norwegian PD cases (in total 1,139 cases), one of the originally reported [172] mutations was identified in three US sporadic cases, but none of the other mutations were found [258].…”

Non-synonymous GIGYF2 variants in Parkinson’s disease from two Asian populations

“…The current debate regarding the signiWcance of the heterozygous GIGYF2 variants reported by Lautier et al (2008) is confounded by the fact that the limited segregation data presented for aVected families was neither robust nor convincing enough compared to LRRK2 and other PD genes, and the incomplete penetrance would require longitudinal evaluation. In a detailed followup genetic study in Portugal and American cohorts, Bras et al (2009) detected 46 variants, the majority of which were present in both PD and controls but none were associated with PD. More importantly, two variants (N478T and L1230_Q1237del) thought to be pathogenic by Lautier et al were noted to be present in controls.…”

“…In linkage studies, the highest LOD score of 5.14 was for a D2S206 marker located within the GIGYF2 gene which encodes the Grb10-Interacting GYF Protein 2. Lautier et al (2008) recently sequenced the 27 coding exons of the GIGYF2 gene in 123 Italian and 126 French patients with familial PD and 131 Italian and 96 French controls (Bras et al 2009). They reported seven diVerent GIGYF2 missense mutations and three amino acid insertions or deletions in 16 unrelated PD index patients.…”

Is GIGYF2 the defective gene at the PARK11 locus?

“…Some were present in equal frequencies in both cases and controls and were therefore considered neutral polymorphisms. A few additional rare variants were present only in cases or only in controls, but their overall frequency was not statistically different between the two groups of individuals [16]. Unfortunately, cosegregation between GIGYF2 variants and disease was not explored; nor were functional studies performed.…”

“…A more comprehensive study was performed by sequencing the whole GIGYF2 coding region in 727 PD cases and 911 neurologically healthy controls, including 267 cases and 451 controls from Portugal and 460 casecontrol pairs from the United States [16]. Again, only one of the missense mutations (Asn457Thr) reported by Lautier et al [13••] as pathogenic was detected, and it was only found in one Portuguese control.…”