VPS35 Mutations in Parkinson Disease

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• 作者：Carles Vilariñ ; o-Gü ; ell¹ ; ¹⁵ ; ^{carles@can.ubc.ca"" rel=""nofollow} ; Christian Wider² ; ¹⁵ ; Owen  ; A. Ross³ ; Justus  ; C. Dachsel³ ; Jennifer  ; M. Kachergus³ ; Sarah  ; J. Lincoln³ ; Alexandra  ; I. Soto-Ortolaza³ ; Stephanie  ; A. Cobb³ ; Greggory  ; J. Wilhoite³ ; Justin  ; A. Bacon³ ; Bahareh Behrouz³ ; Heather  ; L. Melrose³ ; Emna Hentati³ ; Andreas Puschmann³ ; ⁴ ; Daniel  ; M. Evans¹ ; Elizabeth Conibear¹ ; Wyeth  ; W. Wasserman¹ ; Jan  ; O. Aasly⁵ ; Pierre  ; R. Burkhard⁶ ; Ruth Djaldetti⁷ ; Joseph Ghika² ; Faycal Hentati⁸ ; Anna Krygowska-Wajs⁹ ; Tim Lynch¹⁰ ; ¹¹ ; Eldad Melamed⁷ ; Alex Rajput¹² ; Ali  ; H. Rajput¹² ; Alessandra Solida² ; Ruey-Meei Wu¹³ ; Ryan  ; J. Uitti¹⁴ ; Zbigniew  ; K. Wszolek¹⁴ ; Franç ; ois Vingerhoets² ; Matthew  ; J. Farrer¹ ; ³
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：15 July 2011
• 年：2011
• 卷：89
• 期：1
• 页码：162-167
• 全文大小：579 K

文摘

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.