β-Mannosidosis mice: a model for the human lysosomal storage disease

Abstract

Beta-mannosidase, a lysosomal enzyme which acts exclusively at the last step of oligosaccharide catabolism in glycoprotein degradation, functions to cleave the unique beta-linked mannose sugar found in all N-linked oligosaccharides of glycoproteins. Deficiency of this enzyme results in beta-mannosidosis, a lysosomal storage disease characterized by the cellular accumulation of small oligosaccharides. In human beta-mannosidosis, the clinical presentation is variable and can be mild, even when caused by functionally null mutations. In contrast, two existing ruminant animal models have disease that is consistent and severe. To further explore the molecular pathology of this disease and to investigate potential treatment strategies, we produced a beta-mannosidase knockout mouse. Homozygous mutant mice have undetectable beta-mannosidase activity. General appearance and growth of the knockout mice are similar to the wild-type littermates. At >1 year of age, these mice exhibit no dysmorphology or overt neurological problems. The mutant animals have consistent cytoplasmic vacuolation in the central nervous system and minimal vacuolation in most visceral organs. Thin-layer chromatography demonstrated an accumulation of disaccharide in epididymis and brain. This mouse model closely resembles human beta-mannosidosis and provides a useful tool for studying the phenotypic variation in different species and will facilitate the study of potential therapies for lysosomal storage diseases.

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…Using the protein atlas 59 and Illumina Body Map (GEO: GSE30611), we found that the reproductive tract and the kidney both have intermediate expression of MANBA (not shown), and MANBA is expressed in lysosome of kidney tubule cells ( Figure 4A). 60 Segment-specific expression data obtained from rat kidneys 61 indicate that Manba is expressed in the loop of Henle, with the highest expression level in medullary collecting duct segment.…”

A Clinically Severe Variant of β-Mannosidosis, Presenting with Neonatal Onset Epilepsy with Subsequent Evolution of Hydrocephalus

“…This has in part been attributed to the fact that b-mannosidosis deficient ruminants accumulate the trisaccharide Man(b1-4) GlcNAc (b1-4) GlcNAc to a greater extent than the disaccharide Man(b1-4) GlcNAc (Jones et al 1992). However humans who, like other nonruminants, have an additional lysosomal enzyme chitobiase (Zhu et al 2006) accumulate the disaccharide (Cooper et al 1988). This potential correlation between phenotype and predominating oligosaccharide is strengthened by the fact that the mouse model, where predominately disaccharides accumulate, also exhibits a mild phenotype with no obvious dysostosis (Zhu et al 2006).…”

“…However humans who, like other nonruminants, have an additional lysosomal enzyme chitobiase (Zhu et al 2006) accumulate the disaccharide (Cooper et al 1988). This potential correlation between phenotype and predominating oligosaccharide is strengthened by the fact that the mouse model, where predominately disaccharides accumulate, also exhibits a mild phenotype with no obvious dysostosis (Zhu et al 2006).…”

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

“…A mouse model of b-mannosidosis was created by targeted disruption of the b-mannosidase gene by homologous recombination in 129X1/SvJ ES cells (Zhu et al 2006). Homozygous mutant animals had the expected enzyme deficiency and had accumulation of disaccharide in brain tissue, but showed normal growth, appearance, and lifespan.…”

“…Previous examination of mutant animals between 1 and 9 months of age showed selective, variable neuronal vacuolation with no hypomyelination, closer to what would be expected in the human b-mannosidosis phenotype given the human clinical presentation. Cell populations identified with variable vacuolation included pyramidal cells (layer V) in dorsolateral cortex, choroid plexus, specific segments of Ammon's horn, striatum, amygdala, deep cerebellar nuclei, and spinal cord (Zhu et al 2006).…”