PARK11 gene (GIGYF2) variants Asn56Ser and Asn457Thr are not pathogenic for Parkinson's disease

Zimprich, Alexander; Schulte, Claudia; Reinthaler, Eva M.; Haubenberger, Dietrich; Balzar, Jorg; Lichtner, Peter; Tawil, Salwa El; Edris, Sherif; Foki, Thomas; Pirker, Walter; Katzenschlager, Regina; Daniel, Gerhard; Brücke, Thomas; Auff, Eduard; Gasser, Thomas

doi:10.1016/j.parkreldis.2009.01.005

Cited by 31 publications

(18 citation statements)

References 16 publications

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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.…”

Section: Autosomal Dominant Genes and Loci With Unclear Pathogenicitymentioning

confidence: 99%

Genetic basis of Parkinson's disease: inheritance, penetrance, and expression

Schulte

Gasser

2011

TACG

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Parkinson’s disease can be caused by rare familial genetic mutations, but in most cases it is likely to result from an interaction between multiple genetic and environmental risk factors. Over recent years, many variants in a growing number of genes involved in the pathogenesis of Parkinson’s disease have been identified. Mutations in several genes have been shown to cause familial parkinsonism. In this review, we discuss 12 of them (SNCA, LRRK2, Parkin, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, UCHL1, GIGYF2, HTRA2, and EIF4G1). Additionally, six genes have been shown conclusively to be risk factors for sporadic Parkinson’s disease, and are also discussed (GBA, MAPT, BST1, PARK16, GAK, and HLA). Many more genes and genetic loci have been suggested, but need confirmation. There is evidence that pathways involved in the rare familial forms also play a role in the sporadic form, and that the respective genes might also be risk factors for sporadic Parkinson’s disease. The identification of genes involved in the development of Parkinson’s disease will improve our understanding of the underlying molecular mechanisms, and will hopefully lead to new drug targets and treatment strategies.

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Section: Autosomal Dominant Genes and Loci With Unclear Pathogenicitymentioning

confidence: 99%

Genetic basis of Parkinson's disease: inheritance, penetrance, and expression

Schulte

Gasser

2011

TACG

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“…There was no evidence of segregation of the variants with PD in these families and no increased risk for PD associated with these variants. Zimprich et al (2009) highlighted the presence of two variants (Asn56Ser and Asn457Thr, originally reported by Lautier et al 2008) in both PD patients and controls in their screen of 669 PD patients and 1051 controls. Sutherland et al (2008) analyzed 12 tagging single nucleotide polymorphisms but found no association of any haplotypes of the gene with sporadic PD in Australia.…”

Section: Discussionmentioning

confidence: 74%

“…They reported seven diVerent GIGYF2 missense mutations and three amino acid insertions or deletions in 16 unrelated PD index patients. However, the pathogenicity of some of these mutations has been questioned by other authors (Vilariño-Güell et al 2009;Sutherland et al 2008;Nichols et al 2009;Zimprich et al 2009). These observations, as well as the possibility of ethnicity-speciWc diVerences of these mutations and the current lack of data among Asians prompted us to conduct a genetic analysis of the GIGYF2 gene in the two Asian countries.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Mutations in the GIGYF2 gene at the PARK11 locus have recently been reported in Parkinson's disease (PD). However, the pathogenicity of some of these mutations has been debated. We conducted a comprehensive genetic analysis of the entire GIGYF2 gene in a cohort of young onset and familial PD patients, followed up with screening of specific variants in a separate group of PD and healthy controls. A total of 850 study subjects [450 Parkinson's disease (PD) patients and 400 controls] from two Asian countries were included. Our analysis revealed 17 variants distributed across the entire GIGYF2 gene. Ten of these were novel variants out of which eight were non-synonymous (all heterozygous). Out of these eight, half were novel polymorphic variants (0.2-2%) whereas four were novel non-synonymous variants which were not detected in healthy controls. The seven PD patients with non-synonymous variants had a mean age and age at onset of 55.3 and 50.9 years. All had typical features of PD and only one had a positive family history. The collective frequency of these non-synonymous variants was higher in PD compared to controls (1.6 vs. 0%, P = 0.016, relative risk 1.9, 95% CI 1.2, 1.9). None of the previously reported pathogenic mutations in Italian and French patients were present in our cohort. Our data suggest that GIGYF2 is unlikely to play a major role in our Asian populations. Rare non-synonymous variants appeared to be enriched in our PD patients compared to healthy controls. However, in vivo functional studies and segregation analysis in large pedigrees will be needed to determine if these single heterozygous variants represent rare mutations, risk alleles or benign polymorphisms.

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“…12 Since the GIGYF2 gene was first identified, studies in Portuguese, US, Australian, Norwegian, Belgian, Spanish, French, Italian, Japanese, Singaporean and Chinese populations have provided conflicting data on the causal role of this gene. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] However, around half of these studies only analyzed some or all of the reported pathogenic mutations, rather than comprehensively sequencing the GIGYF2 gene. In our previous study, we directly sequenced the GIGYF2 gene and identified nine missense variants and 14 polymorphisms.…”

Section: Introductionmentioning

confidence: 99%