Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease.

Division of Endocrinology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
The American Journal of Human Genetics (Impact Factor: 11.2). 05/2008; 82(4):822-33. DOI: 10.1016/j.ajhg.2008.01.015
Source: PubMed

ABSTRACT The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

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    ABSTRACT: Heterozygous Gigyf2+/- mice exhibits histopathological evidence of neurodegeneration such as motor dysfunction. Several lines of evidence have demonstrated the important role of insulin-like growth factor-1 receptor (IGF1R) signaling pathway in the neuropathogenic process of cognitive impairment, while decreased Grb10-Interacting GYF Protein 2 (GIGYF2) expression can alter IGF1R trafficking and its downstream signaling pathways. Growth factor receptor-bound protein 10 (Grb10), a suppressor of IGF1R pathway, has been shown to play a critical role in regulating diabetes-associated cognitive impairment. It remains unknown whether endogenous GIGYF2 expression contributes to the development of diabetes-associated cognitive impairment. Using streptozotocin (STZ)-induced diabetic mice model, we first demonstrated that a significantly increased level of GIGYF2 expression was correlated with a significant decrease in the expression of phosphorylated IGF1R as well as the phosphorylation of AKT and ERK1/2, two signaling pathways downstream of IGF1R, in the hippocampus of diabetic mice. On the contrary, in situ knockdown of GIGYF2 expression in hippocampus resulted in increased expression of phosphorylated IGF1R expression and correspondingly reversed the down-regulation of ERK1/2 phsophorylation but had no obvious effect on Grb10 expression. Functionally, knockdown of GIGYF2 expression markedly ameliorated diabetes-associated cognitive dysfunction as well as the ultrastructural pathology and abnormal neurobehavioral changes. These results suggest that increased expression of GIGYF2 might contribute to the development of diabetes-associated cognitive disorder via negatively regulating IGF1R signaling pathway. Therefore, down-regulation of GIGYF2 expression may provide a potential novel approach to treat diabetes-associated cognitive impairment caused by aberrant IGF1R signaling pathway.
    PLoS ONE 09/2014; 9(9):e108559. DOI:10.1371/journal.pone.0108559 · 3.53 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects ~2% of the global population aged ≥65 years. Grb10-interacting GYF protein-2 (GIGYF2) can influence the development of PD through the regulation of insulin-like growth factor-1. The aim of the present meta-analysis study was to establish the contribution of GIGYF2 polymorphisms to PD. The study was conducted based on nine eligible studies consisting of 7,246 PD patients and 7,544 healthy controls. The results indicated that the GIGYF2 C.3630A>G polymorphism increased the risk of PD by 37% [P=0.008; odds ratio (OR), 1.37; 95% confidence interval (CI), 1.08-1.73] and that the GIGYF2 C.167G>A polymorphism was significantly associated with PD (P=0.003; OR, 3.67; 95% CI, 1.56-8.68). The meta-analyses of the other five GIGYF2 polymorphisms (C.1378C>A, C.1554G>A, C.2940A>G, C.1370C>A and C.3651G>A) did not reveal any significant associations. The present meta-analyses of the GIGYF2 genetic polymorphisms may provide a comprehensive overview of this PD candidate gene for future studies.
    11/2014; 2(6):886-892. DOI:10.3892/br.2014.324
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