Targeted Disruption of the Lysosomal  -Mannosidase Gene Results in Mice Resembling a Mild form of Human  -Mannosidosis

Abstract

Alpha-mannosidosis is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the lysosomal alpha-mannosidase, which is involved in the degradation of asparagine-linked carbohydrate cores of glycoproteins. An alpha-mannosidosis mouse model was generated by targeted disruption of the gene for lysosomal alpha-mannosidase. Homozygous mutant animals exhibit alpha-mannosidase enzyme deficiency and elevated urinary secretion of mannose-containing oligosaccharides. Thin-layer chromatography revealed an accumulation of oligosaccharides in liver, kidney, spleen, testis and brain. The cellular alterations were characterized by multiple membrane-limited cytoplasmic vacuoles as seen for instance in liver, exocrine pancreas, kidney, thyroid gland, smooth muscle cells, osteocytes and in various neurons of the central and peripheral nervous systems. The morphological lesions and their topographical distribution, as well as the biochemical alterations, closely resemble those reported for human alpha-mannosidosis. This mouse model will be a valuable tool for studying the pathogenesis of inherited alpha-mannosidosis and may help to evaluate therapeutic approaches for lysosomal storage diseases.

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

“…We then assessed whether transgenic knockout mice reflect the human pathology comparable to the conventional alpha‐mannosidase knockout mice15 and are suitable to study the impact of chronic ERT on neuropathology. Therefore, transgenic and nontransgenic knockout mice as well as wild‐type mice were analyzed for storage and secondary pathological changes 8, 16.…”

“…In this experimental set‐up either nontransgenic wild‐type or nontransgenic heterozygote animals served as controls 15. In previous studies, we demonstrated that four biweekly injections of 500 U/kg rhLAMAN were necessary to significantly reduce CNS storage when applied short term 16.…”

“…However, despite the long‐standing dogma that lysosomal enzymes cannot cross the blood‐brain barrier, within recent years, preclinical research has demonstrated the power of specific ERT regimens to even ameliorate CNS pathology. In this paper, we describe the generation of a novel immune‐tolerant mouse model for alpha‐mannosidosis showing histopathological, biochemical and behavioral characteristics comparable to the conventional alpha‐mannosidase knockout mice 15. A similar approach, describing the successful induction of immune tolerance by transgenic expression of an active site mutant in various LSD mouse models has been used by others 25, 26, 27.…”

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

“…In other lysosomal storage disorders, different, but disease-specific, patterns of neuropathology are characteristic. For example, a-mannosidosis (OMIM 248500), caused by mutations in the a-mannosidase (MAN2B1, EC 3.2.1.24, 609458) gene, has been described in cats, cattle, guinea pigs, humans, and knockout mice (Auclair and Hopwood 2007;Blanz et al 2008;Crawley and Walkley 2007;Damme et al 2011;Stinchi et al 1999;Vite et al 2001) and has somewhat different neurological manifestations and neuropathological characteristics depending on the species. Aspartylglucosaminuria (AGU, OMIM 208400) (Dunder et al 2010;Jalanko et al 1998;Kaartinen et al 1996) is caused by mutations in the gene for glycosylasparaginase (AGA, EC 3.5.1.26, 613228), the enzyme necessary for hydrolysis of the proteinoligosaccharide linkage in N-linked glycoproteins.…”

Recent progress in lysosomal α-mannosidase and its deficiency

“…An α-mannosidosis mouse model has been generated by targeted disruption of the gene for MANB (Stinchi et al, 1999). Homozygous mutant mice exhibit enzymatic deficiency and elevated urinary secretion of mannosecontaining oligosaccharides.…”