title: X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities.
abstract: 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.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA Institute of Inherited Metabolic Disorders, Charles University in Prague - 1st Faculty of Medicine, Ke Karlovu 2, Praha 2 160 00, Czech Republic jakub.sikora@lf1.cuni.cz steve.walkley@einstein.yu.edu.
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leddy
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Rose F. Kennedy Intellectual and Developmental Disabilities Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA jakub.sikora@lf1.cuni.cz steve.walkley@einstein.yu.edu.
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
mesh_terms: D000483:Alleles; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D005678:G(M2) Ganglioside / Q000276:immunology; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics*; D009030:Mosaicism; D009154:Mutation; D015835:Ocular Motility Disorders / Q000235:genetics*; D010641:Phenotype; D011689:Purkinje Cells / Q000166:cytology; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000502:physiology
chemical_list: C503961:NHE6 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D005678:G(M2) Ganglioside
keywords: Christianson syndrome; Female heterozygotes; Mosaicism; NHE6 protein; Slc9a6; X-chromosome inactivation