Alternative titles; symbols
ORPHA: 2828; DO: 0111250;
Cytogenetic location: 2p13 Genomic coordinates (GRCh38) : 2:68,400,001-74,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13 | {Parkinson disease 3} | 602404 | 2 |
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see 168600.
Soon after a form of autosomal dominant Parkinson disease was mapped to 4q21-q22 and was shown to be due to mutations in the alpha-synuclein gene (SNCA; 163890), genetic heterogeneity became apparent, as in other families the disorder was not linked to 4q and was not associated with SNCA mutations. Gasser et al. (1998) described a genetic locus on 2p13 in familial parkinsonism with clinical features closely resembling those of sporadic Parkinson disease, including a similar mean age of onset: 59 years in these families, 59.7 years in sporadic PD (Di Rocco et al., 1996). The maximum multipoint lod score for all 6 families in their study was 3.96, considering affected members only. The most likely location of the locus for this form of familial parkinsonism was considered to be at D2S441, with a 100-to-1 likelihood ratio support interval ranging from D2S134 to D2S286, spanning 10.3 cM on 2p13. The maximum 2-point lod score was 3.20 with marker D2S441 at theta = 0.03. Two of the 6 families were genealogically traced to southern Denmark and northern Germany and were found to share a common haplotype, suggesting a founder effect. West et al. (2001) determined that the 2 families reported by Gasser et al. (1998) with the common haplotype shared 8 markers corresponding to a genetic distance of 3.2 cM. Construction of a BAC-based physical map covering the PARK3 locus genotyping 17 microsatellite markers allowed refinement of the minimum common haplotype for PARK3 to a region spanning a physical distance of approximately 2.5 Mb. All 14 known genes within the critical region were sequenced from at least 2 affected persons from each family and no potentially pathogenic mutations were detected, implying that none of these genes are likely candidates for PARK3.
Klein et al. (1999) evaluated 85 German Parkinson disease patients and 85 ethnically matched controls for shared markers on chromosome 2p that might indicate a founder haplotype. No evidence of linkage disequilibrium was found, suggesting that a previously postulated founder mutation on 2p is not a common cause of Parkinson disease in the population studied by Klein et al. (1999). Furthermore, no patient carried the ala30-to-pro change (163890.0002) in the alpha-synuclein gene, supporting earlier findings that mutations in this gene are very rare.
Parkinson disease is characteristically a late-onset neurodegenerative disorder with a mean age at onset of 61 years, but the disorder can range from juvenile cases to cases in the eighth or ninth decade of life. DeStefano et al. (2002) performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives, mainly affected sib pairs. The highest evidence of linkage was found with 2p (maximum multipoint lod = 2.08), a location previously reported as influencing PD affection status. Association between the age at onset of PD and allele 174 of marker D2S1394, located on 2p13, was observed (P = 0.02). This 174 allele was common to the PD haplotype observed in 2 families that showed linkage to PARK3 and had autosomal dominant PD, suggesting that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.
By studying 281 sib pairs with Parkinson disease, Karamohamed et al. (2003) fine-mapped the PARK3 locus to a 2.2-Mb region on chromosome 2p13. Patients with the TT genotype at rs1876487 had an average 7.4-year earlier age at onset compared to patients with the GT or GG genotype (p = 0.005). The authors suggested that the sepiapterin reductase gene (SPR; 182125) may be involved.
Sharma et al. (2006) found that DNA polymorphisms in a highly intercorrelated linkage disequilibrium block that included the SPR gene appeared to be associated with both sporadic and familial Parkinson disease.
Pankratz et al. (2004) found evidence for linkage of PD to a 15-cM region on 2p overlapping the PARK3 locus in a group of 151 PD families with an average age at disease onset of 61.9 years. They obtained a maximum multipoint lod score of 4.8 at marker D2S337.
In index patients from 4 families that define the PARK3 locus, Strauss et al. (2005) found no mutation in the HTRA2 gene, mutations in which cause another form, PARK13 (610297). Indeed, the data of West et al. (2001) narrowing the PARK3 locus exclude the HTRA2 locus.
DeStefano, A. L., Lew, M. F., Golbe, L. I., Mark, M. H., Lazzarini, A. M., Guttman, M., Montgomery, E., Waters, C. H., Singer, C., Watts, R. L., Currie, L. J., Wooten, G. F., and 19 others. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am. J. Hum. Genet. 70: 1089-1095, 2002. [PubMed: 11920285] [Full Text: https://doi.org/10.1086/339814]
Di Rocco, A., Molinari, S. P., Kollmeier, B., Yahr, M. D. Parkinson's disease: progression and mortality in the L-DOPA era. Adv. Neurol. 69: 3-11, 1996. [PubMed: 8615142]
Gasser, T., Muller-Myhsok, B., Wszolek, Z. K., Oehlmann, R., Calne, D. B., Bonifati, V., Bereznai, B., Fabrizio, E., Vieregge, P., Horstmann, R. D. A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nature Genet. 18: 262-265, 1998. [PubMed: 9500549] [Full Text: https://doi.org/10.1038/ng0398-262]
Karamohamed, S., DeStefano, A. L., Wilk, J. B., Shoemaker, C. M., Golbe, L. I., Mark, M. H., Lazzarini, A. M., Suchowersky, O., Labelle, N., Guttman, M., Currie, L. J., Wooten, G. F., and 22 others. A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study. Neurology 61: 1557-1561, 2003. [PubMed: 14663042] [Full Text: https://doi.org/10.1212/01.wnl.0000095966.99430.f4]
Klein, C., Vieregge, P., Hagenah, J., Sieberer, M., Doyle, E., Jacobs, H., Gasser, T., Breakefield, X. O., Risch, N. J., Ozelius, L. J. Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from Northern Germany. Ann. Hum. Genet. 63: 285-291, 1999. [PubMed: 10738540] [Full Text: https://doi.org/10.1046/j.1469-1809.1999.6340285.x]
Pankratz, N., Uniacke, S. K., Halter, C. A., Rudolph, A., Shults, C. W., Conneally, P. M., Foroud, T., Nichols, W. C., Parkinson Study Group. Genes influencing Parkinson disease onset: replication of PARK3 and identification of novel loci. Neurology 62: 1616-1618, 2004. [PubMed: 15136695] [Full Text: https://doi.org/10.1212/01.wnl.0000123112.51368.10]
Sharma, M., Mueller, J. C., Zimprich, A., Lichtner, P., Hofer, A., Leitner, P., Maass, S., Berg, D., Durr, A., Bonifati, V., De Michele, G., Oostra, B., Brice, A., Wood, N. W., Muller-Myhsok, B., Gasser, T., European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD). The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. J. Med. Genet. 43: 557-562, 2006. [PubMed: 16443856] [Full Text: https://doi.org/10.1136/jmg.2005.039149]
Strauss, K. M., Martins, L. M., Plun-Favreau, H., Marx, F. P., Kautzmann, S., Berg, D., Gasser, T., Wszolek, Z., Muller, T., Bornemann, A., Wolburg, H., Downward, J., Riess, O., Schulz, J. B., Kruger, R. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Molec. Genet. 14: 2099-2111, 2005. [PubMed: 15961413] [Full Text: https://doi.org/10.1093/hmg/ddi215]
West, A. B., Zimprich, A., Lockhart, P. J., Farrer, M, Singleton, A., Holtom, B., Lincoln, S., Hofer, A., Hill, L., Muller-Myhsok, B., Wszolek, Z. K., Hardy, J., Gasser, T. Refinement of the PARK3 locus on chromosome 2p13 and the analysis of 14 candidate genes. Europ. J. Hum. Genet. 9: 659-666, 2001. [PubMed: 11571553] [Full Text: https://doi.org/10.1038/sj.ejhg.5200698]