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

K. Duning; D. O. Wennmann; A. Bokemeyer; C. Reissner; H. Wersching; C. Thomas; J. Buschert; K. Guske; V. Franzke; A. Flöel; H. Lohmann; S. Knecht; S. M. Brand; M. Pöter; U. Rescher; M. Missler; P. Seelheim; C. Pröpper; T. M. Boeckers; L. Makuch; R. Huganir; T. Weide; E. Brand; H. Pavenstädt; J. Kremerskothen

doi:10.1038/tp.2013.49

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

K. Duning, D. O. Wennmann, A. Bokemeyer, C. Reissner, H. Wersching, C. Thomas, J. Buschert, K. Guske, V. Franzke, A. Flöel, H. Lohmann, S. Knecht, S. M. Brand, M. Pöter, U. Rescher, M. Missler, P. Seelheim, C. Pröpper, T. M. Boeckers, L. MakuchR. Huganir, T. Weide, E. Brand, H. Pavenstädt, J. Kremerskothen

School of Medicine

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English (US)
Article number	e272
Journal	Translational psychiatry
Volume	3
DOIs	https://doi.org/10.1038/tp.2013.49
State	Published - 2013

Keywords

C2 domain
KIBRA
human cognition
membrane binding
phosphatidylinositols

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

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10.1038/tp.2013.49

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Duning, K., Wennmann, D. O., Bokemeyer, A., Reissner, C., Wersching, H., Thomas, C., Buschert, J., Guske, K., Franzke, V., Flöel, A., Lohmann, H., Knecht, S., Brand, S. M., Pöter, M., Rescher, U., Missler, M., Seelheim, P., Pröpper, C., Boeckers, T. M., ... Kremerskothen, J. (2013). Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance. Translational psychiatry, 3, Article e272. https://doi.org/10.1038/tp.2013.49

Duning, K, Wennmann, DO, Bokemeyer, A, Reissner, C, Wersching, H, Thomas, C, Buschert, J, Guske, K, Franzke, V, Flöel, A, Lohmann, H, Knecht, S, Brand, SM, Pöter, M, Rescher, U, Missler, M, Seelheim, P, Pröpper, C, Boeckers, TM, Makuch, L, Huganir, R, Weide, T, Brand, E, Pavenstädt, H & Kremerskothen, J 2013, 'Common exonic missense variants in the C2 domain of the human KIBRA protein modify lipid binding and cognitive performance', Translational psychiatry, vol. 3, e272. https://doi.org/10.1038/tp.2013.49

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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.",

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AU - Reissner, C.

AU - Wersching, H.

AU - Thomas, C.

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AU - Flöel, A.

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AU - Seelheim, P.

AU - Pröpper, C.

AU - Boeckers, T. M.

AU - Makuch, L.

AU - Huganir, R.

AU - Weide, T.

AU - Brand, E.

AU - Pavenstädt, H.

AU - Kremerskothen, J.

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

Abstract

Keywords

ASJC Scopus subject areas

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