title: Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance.
abstract: The human KIBRA gene has been linked to human cognition through a lead intronic single-nucleotide polymorphism (SNP; rs17070145) that is associated with episodic memory performance and the risk to develop Alzheimer's disease. However, it remains unknown how this relates to the function of the KIBRA protein. Here, we identified two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in exon 15 of the human KIBRA gene to affect cognitive performance, and to be in almost complete linkage disequilibrium with rs17070145. The identified SNPs encode variants of the KIBRA C2 domain with distinct Ca(2+) dependent binding preferences for monophosphorylated phosphatidylinositols likely due to differences in the dynamics and folding of the lipid-binding pocket. Our results further implicate the KIBRA protein in higher brain function and provide direction to the cellular pathways involved.
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Münster, Münster, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Duning
authors.forename: D O
authors.initials: DO
authors.lastname: Wennmann
authors.forename: A
authors.initials: A
authors.lastname: Bokemeyer
authors.forename: C
authors.initials: C
authors.lastname: Reissner
authors.forename: H
authors.initials: H
authors.lastname: Wersching
authors.forename: C
authors.initials: C
authors.lastname: Thomas
authors.forename: J
authors.initials: J
authors.lastname: Buschert
authors.forename: K
authors.initials: K
authors.lastname: Guske
authors.forename: V
authors.initials: V
authors.lastname: Franzke
authors.forename: A
authors.initials: A
authors.lastname: Flöel
authors.forename: H
authors.initials: H
authors.lastname: Lohmann
authors.forename: S
authors.initials: S
authors.lastname: Knecht
authors.forename: S-M
authors.initials: SM
authors.lastname: Brand
authors.forename: M
authors.initials: M
authors.lastname: Pöter
authors.forename: U
authors.initials: U
authors.lastname: Rescher
authors.forename: M
authors.initials: M
authors.lastname: Missler
authors.forename: P
authors.initials: P
authors.lastname: Seelheim
authors.forename: C
authors.initials: C
authors.lastname: Pröpper
authors.forename: T M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: L
authors.initials: L
authors.lastname: Makuch
authors.forename: R
authors.initials: R
authors.lastname: Huganir
authors.forename: T
authors.initials: T
authors.lastname: Weide
authors.forename: E
authors.initials: E
authors.lastname: Brand
authors.forename: H
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: J
authors.initials: J
authors.lastname: Kremerskothen
mesh_terms: D003071:Cognition / Q000502:physiology*; D005091:Exons / Q000235:genetics / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D015810:Linkage Disequilibrium / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology; D009483:Neuropsychological Tests; D010716:Phosphatidylinositols / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010716:Phosphatidylinositols; D010750:Phosphoproteins; C513637:WWC1 protein, human