ORPHA: 411602;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.1 | {Parkinson disease 11} | 607688 | 3 | GIGYF2 | 612003 |
A number sign (#) is used with this entry because of evidence that susceptibility to Parkinson disease-11 (PARK11) is conferred by heterozygous mutation in the GIGYF2 gene (612003) on chromosome 2q37.
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see PD (168600).
Pankratz et al. (2002) reported linkage to 2q in a sample of sib pairs with Parkinson disease. Pankratz et al. (2003) expanded the sample to include 150 families meeting their strictest diagnostic definition of verified Parkinson disease. To delineate further the chromosome 2q linkage, they performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a lod score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggested that variation in a gene on 2q36-q37 contributes to PD susceptibility.
Pankratz et al. (2002) and Pankratz et al. (2003) showed that evidence for a chromosome 2q36-q37 PD susceptibility gene was primarily due to families with verified PD that had a strong family history of PD, defined as at least 4 affected family members or an affected sib pair with an affected parent. In their expanded sample of 362 families, Pankratz et al. (2003) identified 85 families meeting these criteria. A genome screen performed in these 85 families continued to provide strong evidence of linkage to chromosome 2q (lod = 4.9).
In 45 European families with a strong family history of PD, Prestel et al. (2005) did not obtain a significant lod score in the region of 2q36-q37 that had been demonstrated by Pankratz et al. (2002) in a North American population.
Maraganore et al. (2005) performed a 2-tiered, genomewide association study of PD including 443 sib pairs discordant for PD and 332 case-unrelated control pairs. One of the SNPs studied tagged the PARK11 late-onset PD susceptibility locus (p = 1.70 x 10(-5)).
In affected members of 12 unrelated Italian or French families with PD, Lautier et al. (2008) identified 7 different heterozygous mutations in the GIGYF2 gene (see, e.g., 612003.0001-612003.0004). Inheritance was autosomal dominant with evidence of incomplete penetrance. Clinical features were similar to that of idiopathic PD.
Bras et al. (2009) sequenced the entire coding region of GIGYF2 in a series of 267 Portuguese and 460 North American PD samples. The authors found 3 previously published mutations, including N457T (612003.0002), among neurologically normal control individuals. The authors suggested that mutations in GIGYF2 are not strongly related to the development of the disease in either of these populations.
Nichols et al. (2009) did not identify 5 of the 7 GIGYF2 variants reported by Lautier et al. (2008) among 96 probands with PD linked to chromosome 2q or in an extended sample of 566 multiplex PD families. One variant (N56S; 612003.0001) was found in 2 families and showed incomplete penetrance. Another variant (N457T; 612003.0002) was demonstrated not to segregate with the disorder in 1 family, raising doubts about its pathogenicity. Nichols et al. (2009) concluded that there was no consistent evidence that variation in the GIGYF2 gene contributes significantly to PD, and suggested that variation in another gene at this locus accounts for the disorder.
Zimprich et al. (2009) identified the N56S variant in 1 of 669 PD patients and in 1 of 1,051 control individuals. The patient with PD had an affected sister, who did not carry the N56S variant. In addition, the N457T variant was found in 1 patient of Egyptian origin and in 3 controls of European origin, but not in 50 Egyptian controls. The authors concluded that neither variant plays a major role in the pathogenesis of PD.
Tan et al. (2009) identified 4 different heterozygous mutations in the GIGYF2 gene (see, e.g., K421R; 612003.0005) in 7 (1.6%) of 450 patients with Parkinson disease from Taiwan and Singapore. The mutations were not identified in 400 controls. One patient had a positive family history, but the family was too small for segregation analysis. All patients had typical features of PD, with a mean age of onset ranging from 39 to 67 years. None of the mutations reported by Lautier et al. (2008) were found. Tan et al. (2009) emphasized that their results should be interpreted with caution, and that replication studies should be performed to establish conclusively if the variants are indeed pathogenic.
Giovannone et al. (2009) reported that Gigyf2 -/- mice underwent apparently normal embryonic development, but died within the first 2 postnatal days. Gigyf2 +/- mice survived to adulthood with no evident metabolic or growth defects. At 12-15 months of age, the Gigyf2 +/- mice began to exhibit motor dysfunction manifested as decreased balance time on a rotating horizontal rod. This was associated with histopathologic evidence of neurodegeneration and rare intracytoplasmic Lewy body-like inclusions in spinal anterior horn motor neurons. There were alpha-synuclein (SNCA; 163890)-positive neuritic plaques in the brainstem and cerebellum, but no abnormalities in the substantia nigra. Primary cultured embryo fibroblasts from Gigyf2 -/- mice exhibited decreased IGF-I (IGF1; 147440)-stimulated receptor tyrosine phosphorylation and augmented ERK1/2 (see 601795) phosphorylation. Giovannone et al. (2009) proposed an important role of GIGYF2 in age-related neurodegeneration and IGF pathway signaling.
Bras, J., Simon-Sanchez, J., Federoff, M., Morgadinho, A., Januario, C., Ribeiro, M., Cunha, L., Oliveira, C., Singleton, A. B. Lack of replication of association between GIGYF2 variants and Parkinson disease. Hum. Molec. Genet. 18: 341-346, 2009. [PubMed: 18923002] [Full Text: https://doi.org/10.1093/hmg/ddn340]
Giovannone, B., Tsiaras, W. G., de la Monte, S., Klysik, J., Lautier, C., Karashchuk, G., Goldwurm, S., Smith, R. J. GIGYF2 gene disruption in mice results in neurodegeneration and altered insulin-like growth factor signaling. Hum. Molec. Genet. 18: 4629-4639, 2009. [PubMed: 19744960] [Full Text: https://doi.org/10.1093/hmg/ddp430]
Lautier, C., Goldwurm, S., Durr, A., Giovannone, B., Tsiaras, W. G., Pezzoli, G., Brice, A., Smith, R. J. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am. J. Hum. Genet. 82: 822-833, 2008. [PubMed: 18358451] [Full Text: https://doi.org/10.1016/j.ajhg.2008.01.015]
Maraganore, D. M., de Andrade, M., Lesnick, T. G., Strain, K. J., Farrer, M. J., Rocca, W. A., Pant, P. V. K., Frazer, K. A., Cox, D. R., Ballinger, D. G. High-resolution whole-genome association study of Parkinson disease. Am. J. Hum. Genet. 77: 685-693, 2005. [PubMed: 16252231] [Full Text: https://doi.org/10.1086/496902]
Nichols, W. C., Kissell, D. K., Pankratz, N., Pauciulo, M. W., Elsaesser, V. E., Clark, K. A., Halter, C. A., Rudolph, A., Wojcieszek, J., Pfeiffer, R. F., Foroud, T. Variation in GIGYF2 is not associated with Parkinson disease. Neurology 72: 1886-1892, 2009. [PubMed: 19279319] [Full Text: https://doi.org/10.1212/01.wnl.0000346517.98982.1b]
Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Murrell, J., Rudolph, A., Shults, C. W., Conneally, P. M., Foroud, T., Parkinson Study Group. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum. Molec. Genet. 12: 2599-2608, 2003. [PubMed: 12925570] [Full Text: https://doi.org/10.1093/hmg/ddg270]
Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Rudolph, A., Shults, C., Conneally, P. M., Foroud, T., the Parkinson Study Group. Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. Am. J. Hum. Genet. 71: 124-135, 2002. [PubMed: 12058349] [Full Text: https://doi.org/10.1086/341282]
Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Rudolph, A., Shults, C., Conneally, P. M., Foroud, T., the Parkinson Study Group. Significant linkage of Parkinson disease to chromosome 2q36-37. Am. J. Hum. Genet. 72: 1053-1057, 2003. [PubMed: 12638082] [Full Text: https://doi.org/10.1086/374383]
Prestel, J., Sharma, M., Leitner, P., Zimprich, A., Vaughan, J. R., Durr, A., Bonifati, V., De Michele, G., Hanagasi, H. A., Farrer, M., Hofer, A., Asmus, F., Volpe, G., Meco, G., Brice, A., Wood, N. W., Muller-Myhsok, B., Gasser, T., the European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD). PARK11 is not linked with Parkinson's disease in European families. Europ. J. Hum. Genet. 13: 193-197, 2005. [PubMed: 15523496] [Full Text: https://doi.org/10.1038/sj.ejhg.5201317]
Tan, E.-K., Lin, C.-H., Tai, C.-H., Tan, L. C., Chen, M.-L., Li, R., Lim, H.-Q., Pavanni, R., Yuen, Y., Prakash, K. M., Zhao, Y., Wu, R.-M. Non-synonymous GIGYF2 variants in Parkinson's disease from two Asian populations. Hum. Genet. 126: 425-430, 2009. [PubMed: 19449032] [Full Text: https://doi.org/10.1007/s00439-009-0678-x]
Zimprich, A., Schulte, C., Reinthaler, E., Haubenberger, D., Balzar, J., Lichtner, P., El Tawil, S., Edris, S., Foki, T., Pirker, W., Katzenschlager, R., Daniel, G. Brucke, T.; Auff, E.; Gasser, T. PARK11 gene (GIGYF2) variants asn56ser and asn457thr are not pathogenic for Parkinson's disease. Parkinsonism Relat. Disord. 15: 532-534, 2009. [PubMed: 19250854] [Full Text: https://doi.org/10.1016/j.parkreldis.2009.01.005]