ORPHA: 411602; DO: 0060897;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q11.2 | {Parkinson disease 17} | 614203 | Autosomal dominant | 3 | VPS35 | 601501 |
A number sign (#) is used with this entry because of evidence that Parkinson disease-17 (PARK17) is caused by heterozygous mutation in the VPS35 gene (601501) on chromosome 16q11.
Parkinson disease-17 (PARK17) is an autosomal dominant, adult-onset form of the disorder. It is phenotypically similar to idiopathic Parkinson disease (summary by Wider et al., 2008).
For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600.
Wider et al. (2008) reported a large family of Swiss origin with autosomal dominant levodopa-responsive Parkinson disease. Age at onset ranged from 42 to 64 years (mean of 52), and most patients presented with resting tremor. Other features included akinesia, tremor, rigidity, and cramps. Most had severe motor fluctuations with dyskinesia and dystonia. Three of 11 affected individuals had learning difficulties, and 1 with mental retardation and schizophrenia became demented at the end of her life. Brain fluorodopa PET scan of 1 patient showed marked asymmetric tracer uptake deficiency. Brain MRIs of 3 patients were normal. Limited neuropathologic examination of 1 patient showed no Lewy bodies and negative staining for alpha-synuclein. The phenotype could not be distinguished from idiopathic Parkinson disease. Known genetic causes of autosomal dominant PD were excluded.
Zimprich et al. (2011) reported a large Austrian family with autosomal dominant adult-onset Parkinson disease. The mean age at onset was 53 years (range, 40-68 years), and presenting symptoms included postural instability, resting tremor, and bradykinesia. All showed clinical improvement after dopaminergic treatment. Age-dependent incomplete penetrance was observed.
Kumar et al. (2012) reported a German man with tremor-dominant levodopa-responsive PARK17 with onset at age 45 years. The disorder was progressive, and he later developed impulse control behaviors, likely due to dopamine-agonist therapy, hyperhidrosis, impaired smell, and mild memory impairment. His deceased father developed PD in his late forties, and a deceased paternal grandfather, deceased paternal uncle, and living paternal aunt were also affected.
The transmission pattern of PARK17 in the family reported by Kumar et al. (2012) was consistent with autosomal dominant inheritance and incomplete penetrance.
By exome sequencing of affected members of the Swiss family with Parkinson disease reported by Wider et al. (2008), Vilarino-Guell et al. (2011) identified a heterozygous mutation in the VPS35 gene (D620N; 601501.0001). Subsequent sequencing of this gene in 4,326 PD patients identified 4 with the same mutation: 3 familial cases and 1 with sporadic disease. Haplotype analysis indicated independent mutational events, suggesting a mutation hotspot.
Simultaneously and independently and by the same method, Zimprich et al. (2011) identified the D620N mutation in affected members of a large Austrian family with autosomal dominant parkinsonism. Two additional carriers of this mutation were found among 486 PD patients in Austria. Zimprich et al. (2011) identified several other possibly pathogenic VPS35 variants in patients with PD, but the evidence was inconclusive.
By targeted sequencing, Kumar et al. (2012) identified heterozygosity for the D620N mutation in 1 of 1,774 patients with Parkinson disease. The patients were ascertained from several tertiary referral centers in Germany, Serbia, Chile, and the United States. Family history of the German mutation carrier revealed an affected paternal aunt who carried the mutation, as well as 3 reportedly unaffected sibs in their fifties and sixties who also carried the mutation, indicating incomplete penetrance. Kumar et al. (2012) concluded that VPS35 mutations are a rare cause of PD, and they estimated a carrier frequency for the D620N mutation of 0.1% among patients with PD.
By whole-exome sequencing targeting the VPS35 gene in 213 patients with Parkinson disease, Nuytemans et al. (2013) found no significant evidence for a major contribution of genetic variability in VPS35 to development of the disorder.
By specific screening for the D620N mutation (601501.0001) among Japanese patients with Parkinson disease, Ando et al. (2012) identified the heterozygous mutation in 3 (1.0%) of 330 patients with autosomal dominant PD and in 1 (0.23%) of 433 patients with sporadic PD. Haplotype analysis suggested at least 3 independent founders in this population, indicating that it may be a mutation hotspot. Patients with this mutation showed typical adult-onset, tremor-predominant PD, with good response to levodopa treatment. The mutation was not found in 1,158 control chromosomes.
Parkinson disease caused by mutation in the VPS35 gene on chromosome 16q12 is designated here as PARK17. Although PARK17 had been used in the literature to refer to a possible locus on chromosome 4p (Hamza et al., 2010), validation for this locus had not yet been achieved (Mata et al., 2011).
Ando, M,, Funayama, M., Li, Y., Kashihara, K., Murakami, Y., Ishizu, N., Toyoda, C., Noguchi, K., Hashimoto, T., Nakano, N., Sasaki, R., Kokubo, Y., Kuzuhara, S., Ogaki, K., Yamashita, C., Yoshino, H., Hatano, T., Tomiyama, H., Hattori, N. VPS35 mutation in Japanese patients with typical Parkinson's disease. Mov. Disord. 27: 1413-1417, 2012. Note: Erratum: Mov. Disord. 35: 2127 only, 2020. [PubMed: 22991136] [Full Text: https://doi.org/10.1002/mds.25145]
Hamza, T. H., Zabetian, C. P., Tenesa, A., Laederach, A., Montimurro, J., Yearout, D., Kay, D. M., Doheny, K. F., Paschall, J., Pugh, E., Kusel, V. I., Collura, R., Roberts, J., Griffith, A., Samii, A., Scott, W. K., Nutt, J., Factor, S. A., Payami, H. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nature Genet. 42: 781-785, 2010. [PubMed: 20711177] [Full Text: https://doi.org/10.1038/ng.642]
Kumar, K. R., Weissbach, A., Heldmann, M., Kasten, M., Tunc, S., Sue, C. M., Svetel, M., Kostic, V. S., Segura-Aguilar, J., Ramirez, A., Simon, D. K., Vieregge, P., Munte, T. F., Hagenah, J., Klein, C., Lohmann, K. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch. Neurol. 69: 1360-1364, 2012. [PubMed: 22801713] [Full Text: https://doi.org/10.1001/archneurol.2011.3367]
Mata, I. F., Yearout, D., Alvarez, V., Coto, E., de Mena, L., Ribacoba, R., Lorenzo-Betancor, O., Samaranch, L., Pastor, P., Cervantes, S., Infante, J., Garcia-Gorostiaga, I., Sierra, M., Combarros, O., Snapinn, K. W., Edwards, K. L., Zabetian, C. P. Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov. Disord. 26: 819-823, 2011. [PubMed: 21425343] [Full Text: https://doi.org/10.1002/mds.23642]
Nuytemans, K., Bademci, G., Inchausti, V., Dressen, A., Kinnamon, D. D., Mehta, A., Wang, L., Zuchner, S., Beecham, G. W., Martin, E. R., Scott, W. K., Vance, J. M. Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 80: 982-989, 2013. [PubMed: 23408866] [Full Text: https://doi.org/10.1212/WNL.0b013e31828727d4]
Vilarino-Guell, C., Wider, C., Ross, O. A., Dachsel, J. C., Kachergus, J. M., Lincoln, S. J., Soto-Ortolaza, A. I., Cobb, S. A., Wilhoite, G. J., Bacon, J. A., Behrouz, B., Melrose, H. L., and 21 others. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89: 162-167, 2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011. [PubMed: 21763482] [Full Text: https://doi.org/10.1016/j.ajhg.2011.06.001]
Wider, C., Skipper, L., Solida, A., Brown, L., Farrer, M., Dickson, D., Wszolek, Z. K., Vingerhoets, F. J. G. Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family. Parkinsonism Relat. Disord. 14: 465-470, 2008. [PubMed: 18342564] [Full Text: https://doi.org/10.1016/j.parkreldis.2007.11.013]
Zimprich, A., Benet-Pages, A., Struhal, W., Graf, E., Eck, S. H., Offman, M. N., Haubenberger, D., Spielberger, S., Schulte, E. C., Lichtner, P., Rossle, S. C., Klopp, N., and 22 others. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89: 168-175, 2011. [PubMed: 21763483] [Full Text: https://doi.org/10.1016/j.ajhg.2011.06.008]