X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities AUTHORS

Christianson syndrome (CS) is an X-linked neurodevelopmental/neurological disorder characterized in males by the following core symptoms that include nonverbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene which encodes a multi-pass 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 (Slc9a6KO) were generated by insertion of the bacterial LacZ/-galactosidase (bGal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations as well as patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6KO mice, bGal 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. Utilizing bGal, we demonstrate mosaic expression of the mutant Slc9a6 allele as well as the mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6KO female mice. At the behavioral level, we show 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 Slc9a6KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and may improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.