Mutations in solute carrier family 9 isoform 6 on chromosome Xq26.3 encoding 
sodium-hydrogen exchanger 6, a protein mainly expressed in early and recycling 
endosomes are known to cause a complex and slowly progressive degenerative human 
neurological disease. Three resulting phenotypes have so far been reported: an 
X-linked Angelman syndrome-like condition, Christianson syndrome and 
corticobasal degeneration with tau deposition, with each characterized by severe 
intellectual disability, epilepsy, autistic behaviour and ataxia. Hypothesizing 
that a sodium-hydrogen exchanger 6 deficiency would most likely disrupt the 
endosomal-lysosomal system of neurons, we examined Slc9a6 knockout mice with 
tissue staining and related techniques commonly used to study lysosomal storage 
disorders. As a result, we found that sodium-hydrogen exchanger 6 depletion 
leads to abnormal accumulation of GM2 ganglioside and unesterified cholesterol 
within late endosomes and lysosomes of neurons in selective brain regions, most 
notably the basolateral nuclei of the amygdala, the CA3 and CA4 regions and 
dentate gyrus of the hippocampus and some areas of cerebral cortex. In these 
select neuronal populations, histochemical staining for β-hexosaminidase 
activity, a lysosomal enzyme involved in the degradation of GM2 ganglioside, was 
undetectable. Neuroaxonal dystrophy similar to that observed in lysosomal 
disease was observed in the cerebellum and was accompanied by a marked and 
progressive loss of Purkinje cells, particularly in those lacking the expression 
of Zebrin II. On behavioural testing, Slc9a6 knockout mice displayed a discrete 
clinical phenotype attributable to motor hyperactivity and cerebellar 
dysfunction. Importantly, these findings show that sodium-hydrogen exchanger 6 
loss of function in the Slc9a6-targeted mouse model leads to compromise of 
endosomal-lysosomal function similar to lysosomal disease and to conspicuous 
neuronal abnormalities in specific brain regions, which in concert could provide 
a unified explanation for the cellular and clinical phenotypes in humans with 
SLC9A6 mutations.