Functional evaluation of autism-associated mutations in NHE9

Kalyan C. Kondapalli, Anniesha Hack, Maya Schushan, Meytal Landau, Nir Ben-Tal, Rajini Rao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number2510
JournalNature Communications
StatePublished - 2013


FundersFunder number
American Physiological Society Porter Physiology Development
National Institutes of HealthR01 DK054214
National Institute of General Medical SciencesT32GM008752
American Heart Association11POST7380034
Israel Science Foundation1775/12
Israeli Centers for Research Excellence


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