Mutation or duplication of the protein coding sequence of the α-synuclein gene (SNCA) can cause autosomal dominant inherited Parkinson disease, but the genetic risk factors for the far more common sporadic form of the disease remain murky. Now, a large collaborative analysis has identified polymorphisms in the SNCA gene promoter that increase the risk of sporadic Parkinson disease. The new findings support the proposition that elevated expression of α-synuclein contributes to PD pathogenesis in the general population, and links pathology of sporadic PD to inherited forms of the disease, both of which feature synuclein-containing inclusions. The results, which appear in the August 9 issue of JAMA, come from the Genetic Epidemiology of Parkinson’s Disease (GEO-PD) Consortium.
On the tau front, three independent studies just out in Nature Genetics report the first examples of deletions of the tau gene in humans. Microdeletions spanning the tau gene and several other genes in the immediate area cause mild mental retardation with characteristic facial features and delayed development. While the studies do not unequivocally identify tau as the cause of the deletion phenotype, the results are consistent with an important role for the protein in normal human development.
Some studies have already pointed to SNCA promoter variants, and in particular, the length of a dinucleotide repeat sequence (REP1), as risk factors for sporadic PD, but the results have been inconsistent. To get a clearer picture, corresponding author Demetrius Maraganore of the Mayo Clinic in Rochester, Minnesota, and the consortium members performed a combined genetic analysis of PD patients from 18 participating sites around the world. Each site reported on genotyping of patients, and provided DNA for a central analysis of a subset of patients. All together, 2,692 patients and 2,652 controls were analyzed—data on about half had been previously published.
The authors identified three common REP1 alleles, consisting of 259, 261, and 263 base pairs. The 263-base-pair allele was significantly associated with PD in the cases versus controls (Odds ratio, 1.43; 95 percent confidence interval, 1.22-1.69; p <.001 for trend). There was also a trend toward reduced disease risk with the shortest allele, the 259-base-pair repeat. The results are consistent with a previous meta-analysis of published studies, except that the strongest effect detected in that analysis was protection by the shorter alleles, with a trend toward increased risk with longer alleles (Mellick et al., 2005).
To more broadly correlate promoter variability and disease, the investigators also analyzed two different single nucleotide polymorphisms. Neither showed any disease association, and only haplotypes that included the longer REP1 variant were associated with PD. Biologically, the results are consistent with increases in synuclein expression conferring risk for PD: Rep1 is major promoter for SNCA expression, and longer REP1 repeats are associated with increased promoter activity in vitro (Chiba-Falek and Nussbaum, 2001).
“Our study demonstrates that the SNCA gene is not only a rare cause of autosomal dominant Parkinson disease in some families, but also a susceptibility gene for Parkinson disease at the population level,” the authors conclude. They estimate that REP1 variability could explain about 3 percent of risk for PD in the general population. While the combination of REP1 with other variants could account for a large part of disease risk, they suggest, the small effect sizes of individual variants illustrates the need for large-scale, carefully standardized studies like this to uncover associations. The results are reminiscent of recent data on the LRRK2 protein: Mutations in the LRRK2 gene cause inherited forms of Parkinson disease but are also found in sporadic cases as well (see ARF related news story).
Tracking down tau, three groups—a British team led by Charles Shaw-Smith, Alan M. Pittman and Lionel Willatt; a group under Bert de Vries in Nijmegen, The Netherlands; and researchers working with Evan Eichler in Seattle, Washington—all took different paths to 17q21.31, the region containing the tau gene. But what they found there was entirely concordant, that a recurrent deletion of the region causes a syndrome of mild mental retardation, distinct facial features, and poor muscle tone. The deletion was present in up to 1 percent of mentally retarded patients, and appeared to result from homologous recombination within a common inversion polymorphism in the area. While gain-of-function mutations in tau are well known for causing frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and other neurodegenerative conditions, this is the first report of humans with tau deficiency. Although the deletion contained at least three other genes, tau represents a good candidate gene for generating the observed phenotype. Tau knockout mice show some muscle weakness and learning problems, and some subtle histological abnormalities in some axons, consistent with a role for human tau in normal development. The findings tentatively suggest that gain and loss of tau functions can lead to very different phenotypes.—Pat McCaffrey
- Mellick GD, Maraganore DM, Silburn PA. Australian data and meta-analysis lend support for alpha-synuclein (NACP-Rep1) as a risk factor for Parkinson's disease. Neurosci Lett. 2005 Feb 28;375(2):112-6. PubMed.
- Chiba-Falek O, Nussbaum RL. Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet. 2001 Dec 15;10(26):3101-9. PubMed.
- Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Krüger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C, . Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006 Aug 9;296(6):661-70. PubMed.
- Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, de Vries BB. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006 Sep;38(9):999-1001. PubMed.
- Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, Stewart H, Price SM, Blair E, Hennekam RC, Fitzpatrick CA, Segraves R, Richmond TA, Guiver C, Albertson DG, Pinkel D, Eis PS, Schwartz S, Knight SJ, Eichler EE. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006 Sep;38(9):1038-42. PubMed.
- Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet. 2006 Sep;38(9):1032-7. PubMed.