Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological 
disorder characterized in males by core symptoms that include non-verbal status, 
intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and 
hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a 
multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, 
functional in early recycling endosomes. The extent and variability of the CS 
phenotype in female heterozygotes, who presumably express the wild-type and 
mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), 
have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) 
were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) 
reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been 
shown to develop late endosomal/lysosomal dysfunction associated with glycolipid 
accumulation in selected neuronal populations and patterned degeneration of 
Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a 
transcriptional/XCI reporter and thus facilitates testing of effects of mosaic 
expression of the mutant allele on penetrance of the abnormal phenotype. Using 
β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and 
mosaically distributed lysosomal glycolipid accumulation and PC pathology in the 
brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed 
that heterozygous female mice suffer from visuospatial memory and motor 
coordination deficits similar to but less severe than those observed in 
X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO 
female mice provide important clues for understanding the likely phenotypic 
range of Christianson syndrome among females heterozygous for SLC9A6 mutations 
and might improve diagnostic practice and genetic counseling by helping to 
characterize this presumably underappreciated patient/carrier group.