RESEARCH ARTICLE A Novel Human Mutation in the SLC9A1 Gene Results in Abolition of Na+/H+ Exchanger Activity

The SLC9A1 gene, the Na+/H+ exchanger isoform 1 is the principal plasmamembrane Na+/H+ exchanger of mammalian cells and functions by exchanging one intracellular proton for one extracellular sodium. The human protein is 815 amino acids in length. Five hundred N-terminal amino acids make up the transport domain of the protein and are believed to form 12 transmembrane segments. Recently, a genetic mutation of the Na+/H+ exchanger isoform 1, N266H, was discovered in a human patient through exome sequencing. We examined the effect of this mutation on expression, targeting and activity of the Na+/H+ exchanger. Mutant N266H protein was expressed in AP-1 cells, which lack their endogenous Na+/H+ exchanger protein. Targeting of the mutant protein to the cell surface was normal and expression levels were only slightly reduced relative to the wild type protein. However, the N266Hmutant pro-tein had no detectable Na+/H+ exchanger activity. A histidine residue at this location may dis-rupt the cation binding site or the pore of the Na+/H+ exchanger protein