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: 10.93). 05/2008; 82(4):822-33. DOI: 10.1016/j.ajhg.2008.01.015
Source: PubMed


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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Available from: Alexandra Durr, Aug 04, 2014
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    • "In addition, a high level of GIGYF2 expression is presented in the pancreas and testis as well as brain (including the hippocampus) of adult mouse, thus supporting a vital role of GIGYF2 in the regulation of IGF1R signaling in the central nervous system (CNS) [15]. Most recently, several lines of evidence have shown that GIGYF2 gene mutations are closely linked to human familial Parkinson's disease [16]–[18], one of the most common neurodegenerative disorders, thus further supporting the notion that GIGYF2 may play a critical role in neuronal degradation in CNS. "
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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.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "This represents a de novo CNV rate of 8.6% (8/93), similar to that which has been seen previously in other non-Chinese CNV studies [2-4,12]. In one female proband (683-3), we discovered a 22-kb deletion at 2q37.1 overlapping GIGYF2, which lies in a susceptibility locus for familial Parkinson's disease [13]. No ASD phenotype has been previously associated with variants affecting this gene. "
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    ABSTRACT: Background Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions with a demonstrated genetic etiology. Rare (<1% frequency) copy number variations (CNVs) account for a proportion of the genetic events involved, but the contribution of these events in non-European ASD populations has not been well studied. Here, we report on rare CNVs detected in a cohort of individuals with ASD of Han Chinese background. Methods DNA samples were obtained from 104 ASD probands and their parents who were recruited from Harbin, China. Samples were genotyped on the Affymetrix CytoScan HD platform. Rare CNVs were identified by comparing data with 873 technology-matched controls from Ontario and 1,235 additional population controls of Han Chinese ethnicity. Results Of the probands, 8.6% had at least 1 de novo CNV (overlapping the GIGYF2, SPRY1, 16p13.3, 16p11.2, 17p13.3-17p13.2, DMD, and NAP1L6 genes/loci). Rare inherited CNVs affected other plausible neurodevelopmental candidate genes including GRID2, LINGO2, and SLC39A12. A 24-kb duplication was also identified at YWHAE, a gene previously implicated in ASD and other developmental disorders. This duplication is observed at a similar frequency in cases and in population controls and is likely a benign Asian-specific copy number polymorphism. Conclusions Our findings help define genomic features relevant to ASD in the Han Chinese and emphasize the importance of using ancestry-matched controls in medical genetic interpretations.
    Full-text · Article · Aug 2014 · Journal of Neurodevelopmental Disorders
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    • "However, APP [23]-[27], Presenilin1/2 [28], [29], tau [30], [31], Apolipoprotein E [32], Cdk5 [33], TDP-43 [34] or GSK-3beta [35], which are implicated in Alzheimer's disease and tauopathy, were not included in these results. Also, alpha-synuclein [36], [37], Leucine-rich repeat kinase 2 [38], [39], ubiquitin carboxyl-terminal hydrolase L1 [40], Parkin [41], Pink1 [42], Grb10-Interacting GYF Protein-2 [43], or Omi/HtrA2 [44], which are implicated in Parkinson's disease, are not included. The postmortem changes in these proteins will also become clear in a future study. "
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    ABSTRACT: Protein phosphorylation is deeply involved in the pathological mechanism of various neurodegenerative disorders. However, in human pathological samples, phosphorylation can be modified during preservation by postmortem factors such as time and temperature. Postmortem changes may also differ among proteins. Unfortunately, there is no comprehensive database that could support the analysis of protein phosphorylation in human brain samples from the standpoint of postmortem changes. As a first step toward addressing the issue, we performed phosphoproteome analysis with brain tissue dissected from mouse bodies preserved under different conditions. Quantitative whole proteome mass analysis showed surprisingly diverse postmortem changes in phosphoproteins that were dependent on temperature, time and protein species. Twelve hrs postmortem was a critical time point for preservation at room temperature. At 4°C, after the body was cooled down, most phosphoproteins were stable for 72 hrs. At either temperature, increase greater than 2-fold was exceptional during this interval. We found several standard proteins by which we can calculate the postmortem time at room temperature. The information obtained in this study will be indispensable for evaluating experimental data with human as well as mouse brain samples.
    Full-text · Article · Jun 2011 · PLoS ONE
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