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BMC Medical Genetics Sep 2009beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene...
BACKGROUND
beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder.
METHODS
Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells.
RESULTS
A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity.
CONCLUSION
Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed.
Topics: Blotting, Western; Cell Line; Child; DNA Mutational Analysis; Dementia, Vascular; Female; Gene Expression; Humans; Male; Mutagenesis, Site-Directed; Mutation, Missense; Pedigree; Transfection; beta-Mannosidase; beta-Mannosidosis
PubMed: 19728872
DOI: 10.1186/1471-2350-10-84 -
The Biochemical Journal Nov 1987The kidneys of man, sheep, cattle and pig were all found to contain 1-aspartamido-beta-acetylglucosamine amidohydrolase activity. However, among these, only human kidney...
The kidneys of man, sheep, cattle and pig were all found to contain 1-aspartamido-beta-acetylglucosamine amidohydrolase activity. However, among these, only human kidney was found to contain endo-beta-N-acetylglucosaminidase activity. The absence of this enzyme in the kidneys of sheep and cattle explains why the oligosaccharides accumulated in, and excreted by, sheep and cattle afflicted with disorders of glycoprotein catabolism (i.e. alpha-mannosidosis and beta-mannosidosis) contain two N-acetylglucosamine residues at the reducing terminus instead of one, as is the case for human patients afflicted with similar disorders.
Topics: Acetylglucosaminidase; Animals; Asialoglycoproteins; Cattle; Chromatography, Gel; Chromatography, Thin Layer; Fibrinogen; Hexosaminidases; Hydrolysis; Kidney; Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; Ovalbumin; Sheep; Species Specificity; Swine
PubMed: 3124807
DOI: 10.1042/bj2480145 -
The Journal of Biological Chemistry May 1981In 1975 a new caprine neurovisceral storage disease was identified in related Nubian goats in Michigan (Jones, M. Z., Cunningham, J. G., Dade, A. W., and Alessi, D. M....
In 1975 a new caprine neurovisceral storage disease was identified in related Nubian goats in Michigan (Jones, M. Z., Cunningham, J. G., Dade, A. W., and Alessi, D. M. (1979) Soc. Neurosci. Abstr. 5, 513). The affected kids of both sexes showed profound neurological deficits at birth, lack of myelination in cerebral hemispheres and cerebellum, axonal lesions, and cytoplasmic vacuolation. A similar genetic syndrome arose independently in a population of Anglo-Nubian goats in New South Wales (Hartley, W. J., and Blakemore, W. F. (1973) Acta Neuropathol. 25, 325-333). Preliminary chemical characterization of an accumulated metabolite was performed. An extract of 1 g of brain from an affected goat was found to contain 2.2 mumol of the trisaccharide Man (beta 1 goes to 4)GlcNAc(beta 1 goes to 4)GlcNAc (beta-mannosylchitobiose). The accumulation of this substance suggests the possibility of a genetic defect in beta-mannosidase in the catabolic pathway for N-linked complex glycopeptides and would be the first indication of a beta-mannosidosis.
Topics: Animals; Brain; Carbohydrate Conformation; Carbohydrate Metabolism, Inborn Errors; Carbohydrate Sequence; Female; Goats; Male; Nervous System Diseases; Oligosaccharides
PubMed: 7228875
DOI: No ID Found -
The Journal of Biological Chemistry May 1987Swainsonine is a potent inhibitor of lysosomal alpha-D-mannosidase, causes the production of hybrid glycoproteins, and is reported to produce a phenocopy of hereditary...
Substrate specificities of rat kidney lysosomal and cytosolic alpha-D-mannosidases and effects of swainsonine suggest a role of the cytosolic enzyme in glycoprotein catabolism.
Swainsonine is a potent inhibitor of lysosomal alpha-D-mannosidase, causes the production of hybrid glycoproteins, and is reported to produce a phenocopy of hereditary alpha-mannosidosis. We now report that the effects of swainsonine administration in the rat are different in two respects from those found in other animals thus far studied. Swainsonine caused the accumulation of oligosaccharide in kidney and urine but not in liver or brain. The accumulated oligosaccharides were mainly Man(alpha 1-3)[Man(alpha 1-6)]Man(beta 1-4)GlcNAc, Man(alpha 1-3)[Man(alpha 1-6)[Man(alpha 1-3)]Man(beta 1-4) GlcNAc, and Man(alpha 1-3)[Man(alpha 1-6)]Man(alpha 1-6)[Man(alpha 1-3)]Man(beta 1-4)GlcNAc. Analogous branched Man4 and Man5 structures are found in pig and sheep tissues, but they are N, N'-diacetylchitobiose derivatives. The substrate specificities of rat kidney lysosomal and cytosolic alpha-D-mannosidases were investigated because in one type of hereditary alpha-mannosidosis, that occurring in man, the major storage products are linear rather than branched oligosaccharides. The lysosomal enzyme showed much greater activity toward linear oligosaccharides than toward the branched oligosaccharides induced in the kidney by swainsonine. On the other hand, cytosolic alpha-D-mannosidase preferred the branched oligosaccharides, a result suggesting that this mannosidase might be inhibitable by swainsonine and that the enzyme might play a normal role in glycoprotein catabolism. Swainsonine was indeed found to inhibit this enzyme at relatively high concentrations (I50 at 100 microM swainsonine), and concentrations of this magnitude were in fact found in the cytosol of kidney of swainsonine-fed rats. The kidney cytosolic alpha-D-mannosidase levels were reduced in these rats and, more important, the accumulated oligosaccharides were present mainly in the cytosol rather than in lysosomes. These results point to possible involvement of cytosolic alpha-D-mannosidase in glycoprotein degradation in the rat.
Topics: Alkaloids; Animals; Cytosol; Glycoproteins; Isoenzymes; Kidney; Kinetics; Lysosomes; Male; Mannosidases; Oligosaccharides; Rats; Rats, Inbred Strains; Substrate Specificity; Swainsonine; alpha-Mannosidase
PubMed: 3106356
DOI: No ID Found -
JIMD Reports 2017Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition....
Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs.
Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.
PubMed: 27469132
DOI: 10.1007/8904_2016_1 -
European Journal of Biochemistry Apr 1990In vitro incubation of the oligomannosyl oligosaccharides Man9GlcNAc and Man5GlcNAc with isolated disrupted lysosomes yields different oligosaccharide isomers resulting...
In vitro incubation of the oligomannosyl oligosaccharides Man9GlcNAc and Man5GlcNAc with isolated disrupted lysosomes yields different oligosaccharide isomers resulting from mannosidase hydrolysis. These isomers were isolated by HPLC and characterized by 1H-NMR spectroscopy. The first steps of the degradation involve an (alpha 1-2)mannosidase activity and lead to the formation of one Man8GlcNAc, one Man7GlcNAc, two Man6GlcNAc and two Man5GlcNAc isomers. These reactions do not require Zn2+ as activator. On the other hand, the following steps, which lead to the formation of Man3GlcNAc and Man2GlcNAc, are Zn2(+)-dependent. This process is characterized by the preferential action of an (alpha 1-3)mannosidase activity, and the formation of Man(alpha 1-6)Man(alpha 1-6)Man(beta 1-4)GlcNAc and Man(alpha 1-6)Man(beta 1-4)GlcNAc. Therefore, the digestion of Man9GlcNAc inside the lysosome appears to follow a very specific pathway, since only nine intermediate compounds can be identified instead of the 38 possible isomers. Our results are consistent both with the existence of several specific enzymes for alpha 1-2, alpha 1-3 and alpha 1-6 linkages, and with the presence of a unique enzyme whose specificity would be dependent either on Zn2+ or on the spatial conformation of the glycan. Nevertheless, previous work on the structural analysis of oligosaccharides excreted in the urine of patients suffering from mannosidosis, demonstrates the absence of the core alpha 1-6-linked mannosyl residue in the major storage product derived from oligomannosyl oligosaccharides. This observation indicates the presence of a specific (alpha 1-6)mannosidase form, unaffected in mannosidosis.
Topics: Animals; Carbohydrate Conformation; Carbohydrate Sequence; Cell Fractionation; Chromatography, High Pressure Liquid; Female; Kinetics; Liver; Lysosomes; Mannosidases; Molecular Sequence Data; Oligosaccharides; Rats; Rats, Inbred Strains; Substrate Specificity
PubMed: 2338081
DOI: 10.1111/j.1432-1033.1990.tb15498.x -
The Journal of Biological Chemistry Apr 1982Liver from goats with an inherited deficiency of beta-D-mannosidase appears only partially deficient in beta-mannosidase (40% of normal values) when assayed with...
Liver from goats with an inherited deficiency of beta-D-mannosidase appears only partially deficient in beta-mannosidase (40% of normal values) when assayed with synthetic beta-mannoside substrates at pH 5.0. Other tissues such as brain and cultured skin fibroblasts show an almost complete deficiency of beta-mannosidase activity. Fractionation of supernatant solutions of normal goat liver on columns of concanavalin A bound to Sepharose 4B resolved beta-mannosidase into a bound (acidic) form (pH optimum, 5.0 to 5.5) and an unbound (neutral) form (broad pH optimum from 5.0 to 8.0). Both forms were heat-labile, inhibited by sodium taurocholate (0.1%) and insensitive to divalent cations such as zinc. However, only the acid lysosomal) form was able to hydrolyze a Man beta GlcNAc beta [3H]GlcNAc trisaccharide. Comparable fractionation of liver from affected goats revealed normal levels of the unbound (neutral) form but a complete absence of the bound (acidic, lysosomal) form. Fractionation of liver from an obligate heterozygote goat revealed normal neutral and 50% of the acidic. These studies suggest that goat liver contains both lysosomal beta-mannosidase (acidic form; deficient in beta-mannosidosis) and nonlysosomal beta-mannosidase (neutral) activity.
Topics: Animals; Goats; Hydrogen-Ion Concentration; Isoenzymes; Kinetics; Liver; Mannosidases; beta-Mannosidase
PubMed: 7061483
DOI: No ID Found -
Analytica Chimica Acta Feb 2011The oligosaccharidoses are a group of metabolic disorders resulting from a deficiency in enzymes responsible for the catabolism of protein bound oligosaccharides and are...
The oligosaccharidoses are a group of metabolic disorders resulting from a deficiency in enzymes responsible for the catabolism of protein bound oligosaccharides and are typified by the accumulation of corresponding sugars in the urine. Screening is typically accomplished using thin layer chromatography. However, analyte specificity can be a problem and thus complicate interpretation of results. For this reason we developed a mixed mode liquid chromatography tandem mass spectrometry assay for the screening of the oligosaccharidoses which potentially mitigates many of the problems associated with thin layer chromatography. Samples from patients previously diagnosed with I-Cell disease, mannosidosis, Pompe, galactosialidosis, and fucosidosis were derivatized with 3-methyl-1-phenyl-2-pyrazolin-5-one and subjected to analysis by liquid chromatography tandem mass spectrometry. Results were compared to normal control samples. Preliminary results suggest that each oligosaccharidoses produces a unique selected reaction monitoring fingerprint and that the developed method may be an effective screening and diagnostic tool for these disorders.
Topics: Antipyrine; Chromatography, High Pressure Liquid; Edaravone; Fucosidosis; Glycogen Storage Disease Type II; Humans; Lysosomal Storage Diseases; Mannosidase Deficiency Diseases; Mucolipidoses; Oligosaccharides; Tandem Mass Spectrometry
PubMed: 21237314
DOI: 10.1016/j.aca.2010.11.047 -
The Journal of Biological Chemistry May 1992A novel lysosomal alpha-mannosidase, with unique substrate specificity, has been partially purified from human spleen by chromatography through concanavalin A-Sepharose,... (Comparative Study)
Comparative Study
A novel lysosomal alpha-mannosidase, with unique substrate specificity, has been partially purified from human spleen by chromatography through concanavalin A-Sepharose, DEAE-Sephadex, and Sephacryl S-300. This enzyme can catalyze the hydrolysis of only 1 mannose residue, that which is alpha(1----6)-linked to the beta-linked mannose in the core of N-linked glycans, as found in the oligosaccharides Man alpha(1----6)[Man alpha(1----3)] Man beta(1----4)GlcNAc and Man alpha(1----6)Man beta(1----4) GlcNAc. The newly described alpha-mannosidase does not catalyze the hydrolysis of mannose residues outside of the core, even if they are alpha(1----6)-linked, and is not active on the other alpha-linked mannose in the core, which is (1----3)-linked. The narrow specificity of the novel mannosidase contrasts sharply with that of the major lysosomal alpha-mannosidase, which is able to catalyze the degradation of oligosaccharides containing diverse linkage and branching patterns of the mannose residues. Importantly, although the major mannosidase readily catalyzes the hydrolysis of the core alpha(1----3)-linked mannose, it is poorly active towards the alpha(1----6)-linked mannose, i.e. the very same mannose residue for which the newly characterized mannosidase is specific. The novel enzyme is further differentiated from the major lysosomal alpha-mannosidase by its inability to catalyze the efficient hydrolysis of the synthetic substrate p-nitrophenyl alpha-mannoside, and by the strong stimulation of its activity by Co2+ and Zn2+. Similarly to the major mannosidase, it is strongly inhibited by swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol, but not by deoxymannojirimycin. The presence of this novel alpha-mannosidase activity in human tissues provides the best explanation, to date, for the structures of the oligosaccharides stored in human alpha-mannosidosis. In this condition the major lysosomal alpha-mannosidase activity is severely deficient, but apparently the alpha(1----6)-mannosidase is unaffected, so that the oligosaccharide structures reflect the unique specificity of this enzyme.
Topics: Animals; Carbohydrate Sequence; Cations, Divalent; Cats; Chromatography, High Pressure Liquid; Humans; Liver; Lysosomes; Mannosidases; Molecular Sequence Data; Oligosaccharides; Pancreas; Sheep; Spleen; Substrate Specificity; Swainsonine
PubMed: 1577805
DOI: No ID Found -
The Canadian Veterinary Journal = La... May 1985Caprine beta-mannosidosis, a fatal inherited deficiency of the lysosomal enzyme beta-mannosidase, was diagnosed in neonatal female Nubian crossbred twin kids from a...
Caprine beta-mannosidosis, a fatal inherited deficiency of the lysosomal enzyme beta-mannosidase, was diagnosed in neonatal female Nubian crossbred twin kids from a small herd near Guelph, Ontario. The kids had been tetraplegic since birth, with whole body tremors, abnormal nystagmus and an intention tremor of the head.At necropsy, the histological lesions found consisted of widespread neuronal and visceral clear cytoplasmic vacuolation. Ultrastructurally, vacuoles were limited by a single membrane, and were empty or contained a small amount of amorphous dense material.Biochemical assay of sera and tissues confirmed negligible levels of beta-mannosidase activity, consistent with those of previously reported cases of caprine beta-mannosidosis.Vacuoles seen with light and electron microscopy are presumed to be lysosomes containing stored disaccharide and trisaccharide, the end products of incomplete catabolism of the oligosaccharide component of certain glycoproteins.
PubMed: 17422528
DOI: No ID Found