Functional evaluation of autism-associated mutations in NHE9

Kalyan C. Kondapalli, Anniesha Hack, Maya Schushan, Meytal Landau, Nir Ben-Tal and Rajini Rao ()
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Kalyan C. Kondapalli: Johns Hopkins University School of Medicine
Anniesha Hack: Johns Hopkins University School of Medicine
Maya Schushan: George S. Wise Faculty of Life Sciences, Tel-Aviv University
Meytal Landau: Technion-Israel Institute of Technology
Nir Ben-Tal: George S. Wise Faculty of Life Sciences, Tel-Aviv University
Rajini Rao: Johns Hopkins University School of Medicine

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract NHE9 (SLC9A9) is an endosomal cation/proton antiporter with orthologues in yeast and bacteria. Rare, missense substitutions in NHE9 are genetically linked with autism but have not been functionally evaluated. Here we use evolutionary conservation analysis to build a model structure of NHE9 based on the crystal structure of bacterial NhaA and use it to screen autism-associated variants in the human population first by phenotype complementation in yeast, followed by functional analysis in primary cortical astrocytes from mouse. NHE9-GFP localizes to recycling endosomes, where it significantly alkalinizes luminal pH, elevates uptake of transferrin and the neurotransmitter glutamate, and stabilizes surface expression of transferrin receptor and GLAST transporter. In contrast, autism-associated variants L236S, S438P and V176I lack function in astrocytes. Thus, we establish a neurobiological cell model of a candidate gene in autism. Loss-of-function mutations in NHE9 may contribute to autistic phenotype by modulating synaptic membrane protein expression and neurotransmitter clearance.

Date: 2013
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DOI: 10.1038/ncomms3510

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