established30. The bacterial and eukaryotic homologues vary significantly in their N-terminal sequences up to and including the third transmembrane helix, and the mammalian protein structure may differ from the NhaA template in this region. In this respect it is noteworthy that cryo-electron microscopy studies of NhaP1 revealed that this archaeal sodium-proton antiporter features thirteen, rather than twelve, transmembrane helices and a different mode of dimerization in comparison to NhaA51. Although more disease-associated variants would need to be analyzed to determine whether such differences are unusual, we can conclude that autism associated NHE9 mutations do impact antiporter function in vitro, and therefore may be causal to disease phenotypes. NHE9 is an eminently druggable target, and it is worth noting that considerable progress has been made in correcting loss of function mutations in CFTR, affecting transporter activity and trafficking, using small molecule potentiators and correctors respectively, in the treatment of cystic fibrosis52.
