Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

• Keywords
• Glycosphingolipids, Lysosomal storage disease, Miglustat, Mucolipidosis type IV, Mucolipin-1, Purkinje cells, Small molecule therapy,
• MeSH
• 1-Deoxynojirimycin analogs & derivatives   therapeutic use   MeSH
• Antigens, CD metabolism   MeSH
• Gliosis drug therapy   etiology   MeSH
• Enzyme Inhibitors therapeutic use   MeSH
• Transient Receptor Potential Channels genetics   metabolism   MeSH
• Lipid Metabolism drug effects   genetics   MeSH
• Disease Models, Animal MeSH
• Cerebellum pathology   MeSH
• Mucolipidoses * complications   genetics   pathology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Exploratory Behavior drug effects   MeSH
• Cell Count MeSH
• Movement Disorders drug therapy   etiology   MeSH
• Nerve Tissue Proteins metabolism   MeSH
• Psychomotor Performance drug effects   MeSH
• Purkinje Cells drug effects   pathology   MeSH
• Retina pathology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 1-Deoxynojirimycin MeSH
• Antigens, CD MeSH
• Enzyme Inhibitors MeSH
• Transient Receptor Potential Channels MeSH
• Mcoln1 protein, mouse MeSH Browser
• miglustat MeSH Browser
• Nerve Tissue Proteins MeSH

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.

• Keywords
• Christianson syndrome, Female heterozygotes, Mosaicism, NHE6 protein, Slc9a6, X-chromosome inactivation,
• MeSH
• Alleles MeSH
• Ataxia genetics   MeSH
• Behavior, Animal MeSH
• Epilepsy genetics   MeSH
• Phenotype MeSH
• G(M2) Ganglioside immunology   MeSH
• Genetic Diseases, X-Linked genetics   MeSH
• Genotype MeSH
• Heterozygote MeSH
• Cognition Disorders genetics   MeSH
• Intellectual Disability genetics   MeSH
• Microcephaly genetics   MeSH
• Disease Models, Animal MeSH
• Mosaicism * MeSH
• Mutation MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Sodium-Hydrogen Exchangers genetics   physiology   MeSH
• Ocular Motility Disorders genetics   MeSH
• Purkinje Cells cytology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• G(M2) Ganglioside MeSH
• Sodium-Hydrogen Exchangers MeSH
• NHE6 protein, mouse MeSH Browser

Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

• MeSH
• Adenosine Triphosphatases metabolism   MeSH
• Analysis of Variance MeSH
• Bromodeoxyuridine MeSH
• Chromatin Immunoprecipitation MeSH
• Chromosomal Proteins, Non-Histone metabolism   MeSH
• Fluorescence MeSH
• Galactosides MeSH
• Histones metabolism   MeSH
• Homeodomain Proteins metabolism   MeSH
• In Situ Hybridization MeSH
• Immunohistochemistry MeSH
• Indoles MeSH
• In Situ Nick-End Labeling MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Rotarod Performance Test MeSH
• Microarray Analysis MeSH
• Morphogenesis genetics   physiology   MeSH
• Cerebellum embryology   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Neural Stem Cells metabolism   physiology   MeSH
• Image Processing, Computer-Assisted MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Purkinje Cells metabolism   MeSH
• Chromatin Assembly and Disassembly physiology   MeSH
• Tolonium Chloride MeSH
• Microscopy, Electron, Transmission MeSH
• Gene Expression Regulation, Developmental genetics   physiology   MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 5-bromo-4-chloro-3-indolyl beta-galactoside MeSH Browser
• Adenosine Triphosphatases MeSH
• Bromodeoxyuridine MeSH
• Chromosomal Proteins, Non-Histone MeSH
• En1 protein, mouse MeSH Browser
• Galactosides MeSH
• Histones MeSH
• Homeodomain Proteins MeSH
• Indoles MeSH
• Smarca5 protein, mouse MeSH Browser
• Tolonium Chloride MeSH