A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease Alexander Zimprich, Anna Benet-Pagès, Walter Struhal,

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A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease Alexander Zimprich, Anna Benet-Pagès, Walter Struhal, Elisabeth Graf, Sebastian H. Eck, Marc N. Offman, Dietrich Haubenberger, Sabine Spielberger, Eva C. Schulte, Peter Lichtner, Shaila C. Rossle, Norman Klopp, Elisabeth Wolf, Klaus Seppi, Walter Pirker, Stefan Presslauer, Brit Mollenhauer, Regina Katzenschlager, Thomas Foki, Christoph Hotzy, Eva Reinthaler, Ashot Harutyunyan, Robert Kralovics, Annette Peters, Fritz Zimprich, Thomas Brücke, Werner Poewe, Eduard Auff, Claudia Trenkwalder, Burkhard Rost, Gerhard Ransmayr, Juliane Winkelmann, Thomas Meitinger, Tim M. Strom The American Journal of Human Genetics Volume 89, Issue 1, Pages 168-175 (July 2011) DOI: 10.1016/j.ajhg.2011.06.008 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Families A, B, and C Unaffected family members are indicated by open symbols, affected members by closed symbols. Asterisks denote individuals genotyped for p.Asp620Asn. To maintain confidentiality, we have not shown genotypes of unaffected individuals. A question mark within a symbol denotes an unknown phenotype. Diagonal bars through symbols denote deceased individuals. The American Journal of Human Genetics 2011 89, 168-175DOI: (10.1016/j.ajhg.2011.06.008) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Hydrogen-Bonding Capacities for Wild-Type Asp620 and Arg524 and the Variants p.Asp620Asn and p.Arg524Trp Hydrogen bonds (HB) are shown as red dashed lines. Asp60 and Arg524 are in green; p.Asp620Asn and p.Arg524Trp are in orange. (A) Asp620 forms a HB to Lys622 and shows an additional salt-bridge interaction. p.Asp620Asn forms fewer HBs, and no electrostatic interaction is possible. (B) Arg524 forms a HB network with Asp483 and Asp486. This network is broken by the p.Arg524Trp substitution. The American Journal of Human Genetics 2011 89, 168-175DOI: (10.1016/j.ajhg.2011.06.008) Copyright © 2011 The American Society of Human Genetics Terms and Conditions