Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance

Kerstin Duning ,Christian Pröpper ,Richard L Huganir ,Christian Thomas ,Carsten Reißner ,Agnes Flöel ,Hermann Pavenstädt ,Hubertus Lohmann ,Stefan-Martin Brand ,Eva Brand ,Markus Missler ,Patrick Seelheim ,Stefan Knecht ,Heike Wersching ,Dirk Oliver Wennmann ,V Franzke ,J Buschert ,Lauren Makuch ,Ursula Rescher ,Thomas Weide ,Arne Bokemeyer ,Katrin Guske ,Tobias M Boeckers ,M Pöter ,Joachim Kremerskothen

doi:10.1038/tp.2013.49

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 Ca2+ 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.

Highlights

KIBRA represents a cytoplasmic protein highly expressed in kidney and brain that was recently linked to higher brain functions,[1,2,3,4,5] presumably based on differences in hippocampal processing.[6,7] Intriguingly, a genome-wide screen for candidate genes affecting human cognitive functions and memory formation revealed an intronic singlenucleotide polymorphism (SNP; rs17070145, residing in the ninth intron of the human KIBRA gene) that was associated with superior performance in episodic memory tasks.[5]
To search for novel genetic variations that may have a functional impact on the KIBRA protein, we performed a screening of the human KIBRA gene by PCR/single stranded conformation polymorphism and subsequent direct sequencing, and identified 21 genetic variants (Figure 1a)
Our biochemical and structural analyses demonstrated that the KIBRA C2 domain has a bona fide lipidbinding capacity with a preference toward PI(3)P that is altered in the variant carrying I734 and A735

Summary

Introduction

KIBRA ( called WWC1 for WW-and-C2-domain–containing-protein-1) represents a cytoplasmic protein highly expressed in kidney and brain that was recently linked to higher brain functions,[1,2,3,4,5] presumably based on differences in hippocampal processing.[6,7] Intriguingly, a genome-wide screen for candidate genes affecting human cognitive functions and memory formation revealed an intronic singlenucleotide polymorphism (SNP; rs17070145, residing in the ninth intron of the human KIBRA gene) that was associated with superior performance in episodic memory tasks.[5]. In contrast to other lipid-binding motifs (for example, Pleckstrin homology domains, Bin–Amphiphysin–Rvs domains, Phox-homology domains, Fab-YOTB-Vac1-EEA1 domains), C2 domains display a unique structure that lacks a defined lipid-binding pocket and a conserved cationic patch.[13] Whereas the majority of known C2 domains have a role in Ca2 þ -dependent vesicle membrane association, these protein modules are involved in Ca2 þ -insensitive membrane targeting as well as in intracellular protein–protein interactions.[13] the function of the KIBRA C2 domain in membrane association has not been analyzed yet, a recent study in null-mutant mice demonstrated that KIBRA is involved in the regulation of the vesicle-based turnover of postsynaptic a-amino-3-hydroxy-5-

Methods

Results

Conclusion