title: Variants in Apaf-1 segregating with major depression promote apoptosome function.
abstract: APAF1, encoding the protein apoptosis protease activating factor 1 (Apaf-1), has recently been established as a chromosome 12 gene conferring predisposition to major depression in humans. The molecular phenotypes of Apaf-1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf-1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell. Cellular phenotypes were measured using a yeast heterologous expression assay in which human Apaf-1 and other proteins necessary to constitute a functional apoptotic pathway were overexpressed. Apaf-1 variants encoded by APAF1 alleles that segregate with major depression in families linked to chromosome 12 shared a common gain-of-function phenotype in both assay systems. In contrast, other Apaf-1 variants showed neutral or loss-of-function phenotypes. The depression-associated alleles thus have a common phenotype that is distinct from that of non-associated variants. This result suggests an etiologic role for enhanced apoptosis in major depression.
authors.affiliation: Advanced Technologies, Abbott Laboratories, 100 Abbott Park Road R424/AP10, Abbott Park, IL 60064, USA.
authors.forename: J
authors.initials: J
authors.lastname: Harlan
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: E
authors.initials: E
authors.lastname: Gubbins
authors.forename: R
authors.initials: R
authors.lastname: Mueller
authors.forename: J-M
authors.initials: JM
authors.lastname: Roch
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authors.lastname: Walter
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authors.initials: M
authors.lastname: Lake
authors.forename: T
authors.initials: T
authors.lastname: Olsen
authors.forename: P
authors.initials: P
authors.lastname: Metzger
authors.forename: S
authors.initials: S
authors.lastname: Dorwin
authors.forename: U
authors.initials: U
authors.lastname: Ladror
authors.forename: D A
authors.initials: DA
authors.lastname: Egan
authors.forename: J
authors.initials: J
authors.lastname: Severin
authors.forename: R W
authors.initials: RW
authors.lastname: Johnson
authors.forename: T F
authors.initials: TF
authors.lastname: Holzman
authors.forename: K
authors.initials: K
authors.lastname: Voelp
authors.forename: C
authors.initials: C
authors.lastname: Davenport
authors.forename: A
authors.initials: A
authors.lastname: Beck
authors.forename: J
authors.initials: J
authors.lastname: Potter
authors.forename: M
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: A
authors.initials: A
authors.lastname: Hahn
authors.forename: B B
authors.initials: BB
authors.lastname: Spear
authors.forename: D N
authors.initials: DN
authors.lastname: Halbert
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: V
authors.initials: V
authors.lastname: Abkevich
authors.forename: C D
authors.initials: CD
authors.lastname: Neff
authors.forename: M H
authors.initials: MH
authors.lastname: Skolnick
authors.forename: D
authors.initials: D
authors.lastname: Shattuck
authors.forename: D A
authors.initials: DA
authors.lastname: Katz
mesh_terms: D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1; D003865:Major Depressive Disorder / Q000235:genetics* / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*
chemical_list: C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins