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VPS35 Mutations in Parkinson Disease

Vilarino-Gueell, Carles; Wider, Christian; Ross, Owen A.; Dachsel, Justus C.; Kachergus, Jennifer M.; Lincoln, Sarah J.; Soto-Ortolaza, Alexandra I.; Cobb, Stephanie A.; Wilhoite, Greggory J. and Bacon, Justin A., et al. (2011) In American Journal of Human Genetics 89(1). p.162-167
Abstract
The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 +/- 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi... (More)
The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 +/- 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD. (Less)
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@article{e8bcea7d-71fc-4760-879f-4a677053021f,
  abstract     = {The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 +/- 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.},
  author       = {Vilarino-Gueell, Carles and Wider, Christian and Ross, Owen A. and Dachsel, Justus C. and Kachergus, Jennifer M. and Lincoln, Sarah J. and Soto-Ortolaza, Alexandra I. and Cobb, Stephanie A. and Wilhoite, Greggory J. and Bacon, Justin A. and Behrouz, Bahareh and Melrose, Heather L. and Hentati, Emna and Puschmann, Andreas and Evans, Daniel M. and Conibear, Elizabeth and Wasserman, Wyeth W. and Aasly, Jan O. and Burkhard, Pierre R. and Djaldetti, Ruth and Ghika, Joseph and Hentati, Faycal and Krygowska-Wajs, Anna and Lynch, Tim and Melamed, Eldad and Rajput, Alex and Rajput, Ali H. and Solida, Alessandra and Wu, Ruey-Meei and Uitti, Ryan J. and Wszolek, Zbigniew K. and Vingerhoets, Francois and Farrer, Matthew J.},
  issn         = {0002-9297},
  language     = {eng},
  number       = {1},
  pages        = {162--167},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {VPS35 Mutations in Parkinson Disease},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2011.06.001},
  volume       = {89},
  year         = {2011},
}