Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Identification of TMEM230 mutations in familial Parkinson's disease

Abstract

Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body–confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mutations in TMEM230 in patients with Parkinson's disease.
Figure 2: Localization of TMEM230 to synaptic vesicles in neurons.
Figure 3: Convergence of TMEM230 and VPS35 in vesicle trafficking and recycling to the TGN.
Figure 4: Impairment of synaptic vesicle trafficking by Parkinson's disease–linked TMEM230 mutants.

Similar content being viewed by others

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Langston, J.W., Schüle, B., Rees, L., Nichols, R.J. & Barlow, C. Multisystem Lewy body disease and the other parkinsonian disorders. Nat. Genet. 47, 1378–1384 (2015).

    Article  CAS  Google Scholar 

  2. Klein, C. & Westenberger, A. Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).

    Article  Google Scholar 

  3. Dawson, T.M., Ko, H.S. & Dawson, V.L. Genetic animal models of Parkinson's disease. Neuron 66, 646–661 (2010).

    Article  CAS  Google Scholar 

  4. Polymeropoulos, M.H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  Google Scholar 

  5. Leroy, E. et al. The ubiquitin pathway in Parkinson's disease. Nature 395, 451–452 (1998).

    Article  CAS  Google Scholar 

  6. Paisán-Ruíz, C. et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595–600 (2004).

    Article  Google Scholar 

  7. Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607 (2004).

    Article  CAS  Google Scholar 

  8. Lautier, C. et al. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am. J. Hum. Genet. 82, 822–833 (2008).

    Article  CAS  Google Scholar 

  9. Strauss, K.M. et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14, 2099–2111 (2005).

    Article  CAS  Google Scholar 

  10. Vilariño-Güell, C. et al. VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89, 162–167 (2011).

    Article  Google Scholar 

  11. Zimprich, A. et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am. J. Hum. Genet. 89, 168–175 (2011).

    Article  CAS  Google Scholar 

  12. Chartier-Harlin, M.C. et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398–406 (2011).

    Article  CAS  Google Scholar 

  13. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    Article  CAS  Google Scholar 

  14. Valente, E.M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    Article  CAS  Google Scholar 

  15. Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003).

    Article  CAS  Google Scholar 

  16. Paisan-Ruiz, C. et al. Characterization of PLA2G6 as a locus for dystonia–parkinsonism. Ann. Neurol. 65, 19–23 (2009).

    Article  Google Scholar 

  17. Shojaee, S. et al. Genome-wide linkage analysis of a Parkinsonian–pyramidal syndrome pedigree by 500 K SNP arrays. Am. J. Hum. Genet. 82, 1375–1384 (2008).

    Article  CAS  Google Scholar 

  18. Krebs, C.E. et al. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum. Mutat. 34, 1200–1207 (2013).

    Article  CAS  Google Scholar 

  19. Quadri, M. et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 34, 1208–1215 (2013).

    Article  CAS  Google Scholar 

  20. Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38, 1184–1191 (2006).

    Article  CAS  Google Scholar 

  21. Edvardson, S. et al. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One 7, e36458 (2012).

    Article  CAS  Google Scholar 

  22. Mata, I.F. et al. The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease. Mol. Neurodegener. 10, 50 (2015).

    Article  Google Scholar 

  23. Anonymous. Key mendelian variants. Nat. Genet. 47, 1371 (2015).

  24. Martin, I., Dawson, V.L. & Dawson, T.M. Recent advances in the genetics of Parkinson's disease. Annu. Rev. Genomics Hum. Genet. 12, 301–325 (2011).

    Article  CAS  Google Scholar 

  25. Kelley, L.A. & Sternberg, M.J. Protein structure prediction on the Web: a case study using the Phyre server. Nat. Protoc. 4, 363–371 (2009).

    Article  CAS  Google Scholar 

  26. Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat. Protoc. 5, 725–738 (2010).

    Article  CAS  Google Scholar 

  27. Källberg, M. et al. Template-based protein structure modeling using the RaptorX web server. Nat. Protoc. 7, 1511–1522 (2012).

    Article  Google Scholar 

  28. Sudhof, T.C. The synaptic vesicle cycle. Annu. Rev. Neurosci. 27, 509–547 (2004).

    Article  Google Scholar 

  29. Bucci, C. et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70, 715–728 (1992).

    Article  CAS  Google Scholar 

  30. Goedert, M., Spillantini, M.G., Del Tredici, K. & Braak, H. 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24 (2013).

    Article  CAS  Google Scholar 

  31. Spillantini, M.G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  CAS  Google Scholar 

  32. Caviston, J.P. & Holzbaur, E.L. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol. 19, 147–155 (2009).

    Article  CAS  Google Scholar 

  33. Song, A.H. et al. A selective filter for cytoplasmic transport at the axon initial segment. Cell 136, 1148–1160 (2009).

    Article  CAS  Google Scholar 

  34. Fuchs, J. et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68, 916–922 (2007).

    Article  CAS  Google Scholar 

  35. Ross, O.A. et al. Genomic investigation of α-synuclein multiplication and parkinsonism. Ann. Neurol. 63, 743–750 (2008).

    Article  CAS  Google Scholar 

  36. Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    Article  CAS  Google Scholar 

  37. Vilariño-Güell, C. et al. DNAJC13 mutations in Parkinson disease. Hum. Mol. Genet. 23, 1794–1801 (2014).

    Article  Google Scholar 

  38. Wszolek, Z.K. et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62, 1619–1622 (2004).

    Article  CAS  Google Scholar 

  39. Spanaki, C., Latsoudis, H. & Plaitakis, A. LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 67, 1518–1519 (2006).

    Article  Google Scholar 

  40. Wider, C. et al. Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family. Parkinsonism Relat. Disord. 14, 465–470 (2008).

    Article  CAS  Google Scholar 

  41. Steger, M. et al. Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. eLife 5, e12813 (2016).

    Article  Google Scholar 

  42. Tardiff, D.F. et al. Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science 342, 979–983 (2013).

    Article  CAS  Google Scholar 

  43. Chung, C.Y. et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013).

    Article  CAS  Google Scholar 

  44. Deng, H.-X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    Article  CAS  Google Scholar 

  45. Nuytemans, K. et al. Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 80, 982–989 (2013).

    Article  CAS  Google Scholar 

  46. Deng, H.-X. et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat. Genet. 42, 165–169 (2010).

    Article  CAS  Google Scholar 

  47. Lathrop, G.M. & Lalouel, J.M. Easy calculations of lod scores and genetic risks on small computers. Am. J. Hum. Genet. 36, 460–465 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Deng, H.X. et al. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc. Natl. Acad. Sci. USA 103, 7142–7147 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the American Parkinson's Disease Association, the US National Institutes of Health (NS074366, NS37167, NS078287, NS094564, AG10133, AG043970 and NS095972), the National Natural Science Foundation of China (81271921, 81430023 and 81471300), the Les Turner ALS Foundation/Herbert and Florence C. Wenske Foundation Professorship, the George Link Jr. Foundation, the Les Turner ALS Foundation and the Foglia Family Foundation. Whole-exome sequencing was performed at the John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine. Imaging work was performed at the Northwestern University Cell Image Facility supported by the National Institutes of Health (CA060553).

Author information

Authors and Affiliations

Authors

Contributions

H.-X.D., A.H.R. and T.S. designed this study. H.-X.D., Y.S., Y.Y., K.B.A., M.A.P.-V. and T.S. performed linkage analysis. H.-X.D., Y.S., Y.Y., K.B.A., C.H., H.Z., S.D., K.N., H.D., B.T., Z.Y., Y.X., P.C., B.H., Z.S., Z.L., J.M.V. and T.S. performed sequencing analysis. H.-X.D., Y.S., N.M., L.C., H.Z., F.F. and Y.-C.M. performed cell culture, immunoblotting, immunohistochemistry and confocal microscopy. N.M. and Y.-C.M. performed primary neuron culture and the trafficking assay. M.J.K. and D.K. performed the SNCA degradation assay. N.J.C. and D.A.N. performed immunogold electron microscopy. N.S. and A.H.R. collected family information and coordinated this study. B.T., Y.X., P.C., X.-P.G., Z.S., Z.L., J.J., J.M.V., O.M., A.H.R. and T.S. performed clinical studies. T.F., B.G. and A.H.R. performed pathological study and provided pathological samples. H.-X.D., A.H.R. and T.S. analyzed the data and wrote the manuscript.

Corresponding authors

Correspondence to Han-Xiang Deng or Teepu Siddique.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–20 and Supplementary Tables 1–5. (PDF 3252 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, HX., Shi, Y., Yang, Y. et al. Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48, 733–739 (2016). https://doi.org/10.1038/ng.3589

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3589

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing