Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome

Abstract

Lichtenstein-Knorr syndrome is an autosomal recessive condition that associates sensorineural hearing loss and cerebellar ataxia. Here, wereport the first identification of a gene involved in Lichtenstein-Knorr syndrome. Byusinga combination of homozygosity mapping and whole-exome sequencing, weidentified the homozygous p.Gly305Arg missense mutation in SLC9A1 that segregates with the disease in a large consanguineous family. Mutant glycine 305 is a highly conserved amino acid present in the eighth transmembrane segment of all metazoan orthologues of NHE1, the Na+/H+ exchanger 1, encoded by SLC9A1. We demonstrate that the p.Gly305Arg mutation causes the nearcomplete de-glycosylation, mis-targeting and loss of proton pumping activityof NHE1. The comparison of our family with the phenotypes of spontaneous and knockout Slc9a1 murinemodels demonstrates that the association between ataxia and hearing loss is caused by complete or near complete loss of function of NHE1 and altered regulation of pHi in the central nervous system.