TY - JOUR
T1 - VPS35 mutations in parkinson disease
AU - Vilariño-Güell, Carles
AU - Wider, Christian
AU - Ross, Owen A.
AU - Dachsel, Justus C.
AU - Kachergus, Jennifer M.
AU - Lincoln, Sarah J.
AU - Soto-Ortolaza, Alexandra I.
AU - Cobb, Stephanie A.
AU - Wilhoite, Greggory J.
AU - Bacon, Justin A.
AU - Bahareh Behrouz, Behrouz
AU - Melrose, Heather L.
AU - Hentati, Emna
AU - Puschmann, Andreas
AU - Evans, Daniel M.
AU - Conibear, Elizabeth
AU - Wasserman, Wyeth W.
AU - Aasly, Jan O.
AU - Burkhard, Pierre R.
AU - Djaldetti, Ruth
AU - Ghika, Joseph
AU - Hentati, Faycal
AU - Krygowska-Wajs, Anna
AU - Lynch, Tim
AU - Melamed, Eldad
AU - Rajput, Alex
AU - Rajput, Ali H.
AU - Solida, Alessandra
AU - Wu, Ruey Meei
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Vingerhoets, François
AU - Farrer, Matthew J.
N1 - Funding Information:
We are grateful to all individuals who generously participated in this study. We thank the Greenberg family for their 2011 AD/PD Conference Award generously donated by Evelyn Greenberg, in memory of Moshe Greenberg. C.V.-G. and exome sequencing were financed by the Parkinson Disease Foundation. Additional funding for clinical, genetic, and functional studies was provided by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS/NIH) (Morris K. Udall Parkinson's Disease Research Center of Excellence; P50NS040256), the Swiss Parkinson's Disease Foundation, and the Michael J. Fox Foundation. Z.K.W. was partially supported by NINDS/NIH grant P50NS072187 and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (to M.J.F. and C.V.-G.). Leading Edge Endowment Funds provided by the Province of British Columbia, LifeLabs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (M.J.F.).
PY - 2011/7/15
Y1 - 2011/7/15
N2 - 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 doparesponsive 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.
AB - 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 doparesponsive 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.
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U2 - 10.1016/j.ajhg.2011.06.001
DO - 10.1016/j.ajhg.2011.06.001
M3 - Article
C2 - 21763482
AN - SCOPUS:80051488602
SN - 0002-9297
VL - 89
SP - 162
EP - 167
JO - American journal of human genetics
JF - American journal of human genetics
IS - 1
ER -