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Mol Med. 2015 Feb 23;21:26-37. doi: 10.2119/molmed.2014.00219.

A Coding Variant of ANO10, Affecting Volume Regulation of Macrophages, Is Associated with Borrelia Seropositivity.

Author information

1
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
2
Institut für Physiologie, Universität Regensburg, Regensburg, Germany.
3
Department of Neurology, University of Ulm, Ulm, Germany.
4
Institute of Virology, Hannover Medical School, Hannover, Germany.
5
National Reference Center for Borrelia, Bavarian Health and Food Safety Authority, Oberschleissheim, Germany.
6
Division of Genome Modifications and Carcinogenesis, Infections and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
7
Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt am Main, Frankfurt/Main, Germany.
8
DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.

Abstract

In a first genome-wide association study (GWAS) approach to anti-Borrelia seropositivity, we identified two significant single nucleotide polymorphisms (SNPs) (rs17850869, P = 4.17E-09; rs41289586, P = 7.18E-08). Both markers, located on chromosomes 16 and 3, respectively, are within or close to genes previously connected to spinocerebellar ataxia. The risk SNP rs41289586 represents a missense variant (R263H) of anoctamin 10 (ANO10), a member of a protein family encoding Cl(-) channels and phospholipid scramblases. ANO10 augments volume-regulated Cl(-) currents (IHypo) in Xenopus oocytes, HEK293 cells, lymphocytes and macrophages and controls volume regulation by enhancing regulatory volume decrease (RVD). ANO10 supports migration of macrophages and phagocytosis of spirochetes. The R263H variant is inhibitory on IHypo, RVD and intracellular Ca(2+) signals, which may delay spirochete clearance, thereby sensitizing adaptive immunity. Our data demonstrate for the first time that ANO10 has a central role in innate immune defense against Borrelia infection.

PMID:
25730773
PMCID:
PMC4461583
DOI:
10.2119/molmed.2014.00219
[Indexed for MEDLINE]
Free PMC Article

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