Recent progress in lysosomal α-mannosidase and its deficiency

Abstract

Lysosomal α-mannosidase (EC 3.2.1.24) is a major exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease, α-mannosidosis, which has been described in humans, cattle, domestic cats and guinea pigs. Recently, great progress has been made in studying the enzyme and its deficiency. This includes cloning of the gene encoding the enzyme, characterization of mutations related to the disease, establishment of valuable animal models, and encouraging results from bone marrow transplantation experiments.

Exploration of the extracellular space by a large-scale secretion screen in the early Xenopus embryo

“…Lysosomal β-Hexosaminidases are indispensable for degradation of gangliosides (an essential class of outer-layer membrane lipids) and mutations in the human β-Hexosaminidase B subunit cause the lysosomal storage disorder Sandhoff disease (Maier et al, 2003). The isolation of both enzymes in our secretion screen is not surprising, given that secretion of α-Mannosidase has been reported from cultured cells (Sun and Wolfe, 2001) and β-Hexosaminidase B has been found in human serum (Isaksson and Hultberg, 1995 We isolated the Xenopus homolog of CHMP1 (charged multivesicular body protein-1) that localizes to the endosome and plays a role in vesicle trafficking (Howard et al, 2001). The Rab-GDP-dissociation inhibitor (RabGDI) modulates membrane association of various Rab GTPases, which are key regulators of vesicular protein transport (Bartz et al, 2003).…”

“…We identified two new Xenopus homologs of lysosomal glycosidases (α-Mannosidase and β-Hexosaminidase B). α-Mannosidase is required for degradation of asparagine-linked carbohydrates of glycoproteins and its deficiency in human and other mammals results in the lysosomal storage disorder α-mannosidosis (Sun and Wolfe, 2001). Lysosomal β-Hexosaminidases are indispensable for degradation of gangliosides (an essential class of outer-layer membrane lipids) and mutations in the human β-Hexosaminidase B subunit cause the lysosomal storage disorder Sandhoff disease (Maier et al, 2003).…”

T-cell-depleted peripheral blood stem cell transplantation for α-mannosidosis

“…The impaired degradation of glycoproteins leads to accumulation of oligosaccharides in multiple tissues including central nervous system (CNS), liver and bone marrow. [1][2][3] Clinically, a-mannosidosis presents with progressive mental deterioration, dysostosis multiplex, impaired hearing, immunodeficiency and coarse facial features. A continuum of clinical severity is observed between type I (infantile onset), with symptoms usually occurring before the age of 12 months with progressive deterioration and death between 3 and 12 years of age, and type II (juvenile onset) with milder symptoms and normal life expectancy.…”

“…6,7,18 Therefore stem cell transplantation represents a good therapeutic option for these patients. 3,6,8 CD34 + PBSCT is a feasible option to reduce the risk of GVHD, but may carry an increased risk for graft rejection. As outlined, transplantation results can be expected to be best when carried out in early childhood.…”

Apparent Diffusion Coefficient Reveals Gray and White Matter Disease, and T2 Mapping Detects White Matter Disease in the Brain in Feline Alpha-Mannosidosis

“…2 Naturally occurring AMD has also been described in cattle, cats, and guinea pigs, and a knockout mouse has been created. [3][4][5][6][7][8][9][10] AMD cats have essentially the same clinical, biochemical, and neuropathologic abnormalities as human patients 11 and have a severe clinical phenotype with grossly obvious neurologic signs, a generally uniform disease course, and death by 6 months without treatment. 12 The feline model has proved to be useful in the evaluation of experimental therapies including bone marrow transplantation and gene therapy.…”