Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease

Frank P. Marx, Carsten Holzmann, Karsten M. Strauss, Lei Li, Olaf Eberhardt, Ellen Gerhardt, Mark R. Cookson, Dena Hernandez, Matt J. Farrer, Jennifer Kachergus, Simone Engelender, Christopher A. Ross, Klaus Berger, Ludger Schöls, Jörg B. Schulz, Olaf Riess, Rejko Krüger

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120 Scopus citations


Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an α-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.

Original languageEnglish (US)
Pages (from-to)1223-1231
Number of pages9
JournalHuman molecular genetics
Issue number11
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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