VPS35 mutations in parkinson disease

Carles Vilariño-Güell, Christian Wider, Owen A Ross, Justus C. Dachsel, Jennifer M. Kachergus, Sarah J. Lincoln, Alexandra I. Soto-Ortolaza, Stephanie A. Cobb, Greggory J. Wilhoite, Justin A. Bacon, Behrouz Bahareh Behrouz, Heather L Melrose, Emna Hentati, Andreas Puschmann, Daniel M. Evans, Elizabeth Conibear, Wyeth W. Wasserman, Jan O. Aasly, Pierre R. Burkhard, Ruth Djaldetti & 13 others Joseph Ghika, Faycal Hentati, Anna Krygowska-Wajs, Tim Lynch, Eldad Melamed, Alex Rajput, Ali H. Rajput, Alessandra Solida, Ruey Meei Wu, Ryan J. Uitti, Zbigniew K Wszolek, François Vingerhoets, Matthew J. Farrer

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)162-167
Number of pages6
JournalAmerican Journal of Human Genetics
Volume89
Issue number1
DOIs
StatePublished - Jul 15 2011

Fingerprint

Parkinson Disease
Recycling
Protein Transport
Mutation
Membrane Proteins
Exome
Inborn Genetic Diseases
Wnt Signaling Pathway
Asparagine
Endosomes
Parkinsonian Disorders
Tremor
Hydrolases
Pedigree
Lysosomes
Aspartic Acid
Virulence
Technology
Acids
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Vilariño-Güell, C., Wider, C., Ross, O. A., Dachsel, J. C., Kachergus, J. M., Lincoln, S. J., ... Farrer, M. J. (2011). VPS35 mutations in parkinson disease. American Journal of Human Genetics, 89(1), 162-167. https://doi.org/10.1016/j.ajhg.2011.06.001

VPS35 mutations in parkinson disease. / Vilariño-Güell, 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.; Bacon, Justin A.; Bahareh Behrouz, Behrouz; Melrose, Heather L; Hentati, Emna; Puschmann, Andreas; Evans, Daniel M.; Conibear, Elizabeth; Wasserman, Wyeth W.; Aasly, Jan O.; Burkhard, Pierre R.; Djaldetti, Ruth; Ghika, Joseph; Hentati, Faycal; Krygowska-Wajs, Anna; Lynch, Tim; Melamed, Eldad; Rajput, Alex; Rajput, Ali H.; Solida, Alessandra; Wu, Ruey Meei; Uitti, Ryan J.; Wszolek, Zbigniew K; Vingerhoets, François; Farrer, Matthew J.

In: American Journal of Human Genetics, Vol. 89, No. 1, 15.07.2011, p. 162-167.

Research output: Contribution to journalArticle

Vilariño-Güell, C, Wider, C, Ross, OA, Dachsel, JC, Kachergus, JM, Lincoln, SJ, Soto-Ortolaza, AI, Cobb, SA, Wilhoite, GJ, Bacon, JA, Bahareh Behrouz, B, Melrose, HL, Hentati, E, Puschmann, A, Evans, DM, Conibear, E, Wasserman, WW, Aasly, JO, Burkhard, PR, Djaldetti, R, Ghika, J, Hentati, F, Krygowska-Wajs, A, Lynch, T, Melamed, E, Rajput, A, Rajput, AH, Solida, A, Wu, RM, Uitti, RJ, Wszolek, ZK, Vingerhoets, F & Farrer, MJ 2011, 'VPS35 mutations in parkinson disease', American Journal of Human Genetics, vol. 89, no. 1, pp. 162-167. https://doi.org/10.1016/j.ajhg.2011.06.001
Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ et al. VPS35 mutations in parkinson disease. American Journal of Human Genetics. 2011 Jul 15;89(1):162-167. https://doi.org/10.1016/j.ajhg.2011.06.001
Vilariño-Güell, 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. ; Bacon, Justin A. ; Bahareh Behrouz, Behrouz ; Melrose, Heather L ; Hentati, Emna ; Puschmann, Andreas ; Evans, Daniel M. ; Conibear, Elizabeth ; Wasserman, Wyeth W. ; Aasly, Jan O. ; Burkhard, Pierre R. ; Djaldetti, Ruth ; Ghika, Joseph ; Hentati, Faycal ; Krygowska-Wajs, Anna ; Lynch, Tim ; Melamed, Eldad ; Rajput, Alex ; Rajput, Ali H. ; Solida, Alessandra ; Wu, Ruey Meei ; Uitti, Ryan J. ; Wszolek, Zbigniew K ; Vingerhoets, François ; Farrer, Matthew J. / VPS35 mutations in parkinson disease. In: American Journal of Human Genetics. 2011 ; Vol. 89, No. 1. pp. 162-167.
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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 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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AU - Ross, Owen A

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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.

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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.

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