Mannosidosis: Separation and Characterization of Two
Acid α-Mannosidase Forms in Mutant Fibroblasts

Burton, Barbara K.; Nadler, Henry L.

doi:10.1159/000458546

Cited by 8 publications

(3 citation statements)

References 14 publications

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“…In addition to clinical heterogeneity, biochemical and roentgenographic heterogeneity have been described. Burton & Nadler (1978) found variable Km's for amannose among mutant skin fibroblast cell lines suggesting multiple allelic variations in a-mannosidase. Some type I1 homozygotes have been shown to have only a partial deficiency of a-mannosidase (Bach et al 1978).…”

Section: Discussionmentioning

confidence: 91%

Mannosidosis: two brothers with different degrees of disease severity

et al. 1981

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Two siblings with different degrees of mental retardation, skeletal dysplasia, coarse facies, delayed speech, motor incoordination, recurrent respiratory infections, and immunological abnormalities, were found to have deficient alpha‐mannosidase activity. Cultured skin fibroblasts in one sib were markedly deficient in alpha‐mannosidase while all other lysosomal enzymes tested were within the normal range. The more severely affected sib came to autopsy and was found to have “washed‐out” appearing cortical neurons and marked histiocytosis effacing lymph node architecture and partially replacing the bone marrow. The post‐mortem brain and liver samples demonstrated a deficiency in alpha‐mannosidase relative to the elevations of other lysosomal enzymes. Although the patterns of abnormalities in the two cases closely match those of descriptions of “type II” and “type I” mannosidosis respectively, the variation should be due to genetic modifiers or environmental effects since the brothers must have shared similar alpha‐mannosidase mutations. Immunologic abnormalities present in the more severely affected sib suggest that the differential survival seen in mannosidosis types I and II may be due to differences in their immune systems.

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Section: Discussionmentioning

confidence: 91%

Mannosidosis: two brothers with different degrees of disease severity

et al. 1981

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“…For example, several investigators have shown that normal a-mannosidase A and B were stimulated by zinc ions in vitro (37,38). Zinc also was found to enhance the residual acidic a-mannosidase activity in various sources from patients with mannosidosis (37)(38)(39)(40). However, a clinical trial of oral zinc supplementation did not alter the level ofresidual activity in plasma, leukocytes, or tears from the treated patients (41).…”

Section: Discussionmentioning

confidence: 99%

Mucopolysaccharidosis type I subtypes. Presence of immunologically cross-reactive material and in vitro enhancement of the residual alpha-L-iduronidase activities.

Schuchman

Desnick²

1988

J. Clin. Invest.

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The enzymatic and immunologic properties of the defective residual a-L-iduronidase activities were investigated in fibroblast extracts from the three subtypes of mucopolysaccharidosis type I, Hurler (MPS IH), Scheie (MPS IS), and HurlerScheie (MPS IH-S) diseases. Using 4-methylumbelliferyl-a-L-iduronide (4MU-a-Id), the activities in fibroblast extracts from all three subtypes were less than 0.1% of normal. Rocket immunoelectrophoresis with monospecific rabbit anti-human a-L-iduronidase polyclonal antibodies, as well as immunoblots using a monoclonal antibody, revealed the presence of crossreactive immunologic material (CRIM) in extracts prepared from each subtype. When the samples were equalized for 8-hexosaminidase A activity, 38-105% of normal enzyme protein was detected. The sequential addition of cystamine, MgCl2 and pyridoxal phosphate increased the residual 4MU-a-Id activities in subtype extracts up to about 35% of normal mean fibroblast activity. Cystamine, MgC2 or pyridoxal phosphate alone enhanced the residual activities two-to fourfold, whereas the sequential addition of all three compounds was required for maximal effect. Of the six B6 vitamers evaluated, only the negatively charged forms, pyridoxamine (PLN), pyridoxamine phosphate (PNP), and pyridoxal phosphate (PLP), stimulated the residual activities. The addition of dermatan sulfate or heparan sulfate to the subtype extracts, followed by treatment with the effector compounds, similarly inhibited both the normal and enhanced MPS I activities. Heat inactivation experiments confirmed the fact that the mutant iduronidase activity was reconstituted and that the observed increase in enzymatic activity was not an artifact of the fluorogenic assay. These results suggest that the presence of certain thiol reducing agents, divalent cations and negatively charged B6 vitamers can alter the conformation of the mutant ac-L-iduronidase in vitro such that the hydrolysis of 4MU-a-Id is enhanced into the heterozygote range.

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“…An inherited deficiency of acidic (~-mannosidase (A and B) causes the lysosomal storage disease in which cytosolic and Golgi mannosidases are unaffected (Carroll et al, 1972;Andria and Sly, 1981). The properities of the residual acid c~-mannosidase in human and cattle have been studied in tissue homogenates and cultured fibroblasts (Beaudet and Nichols, 1976;Desnick et aI., 1976;Philips et al, 1977;Burditt et al, 1978;Burton and Nadler, 1978;Poenaru et al, 1980;Ben-Yoseph et al, 1982). This residual activity showed abnormally high K m for the fluorogenic substrate and decreased thermal stablity.…”

Section: Time (Mi Nutes)mentioning

confidence: 99%

Characterization of α‐mannosidase in feline mannosidosis

Raghavan

Stuer

Rivière

et al. 1987

J of Inher Metab Disea

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Acidic alpha-mannosidase deficiency has been identified in a family of Blue Persian cats. Characterization of the residual activity revealed that the Km for the substrate, 4-methylumbelliferyl-alpha-D-mannoside, increased approximately three-fold with a severe deficiency in Vmax (1-2%) in homogenates of liver and brain of affected cats compared with controls. The residual activity at pH 4.0 in liver homogenates from affected cats is very thermolabile at 51 degrees C while the control activity is stable at this temperature for 1 h. Subcellular fractionation of liver was performed from a control and diseased cat in order to compare the properties of the different alpha-mannosidases localized in these fractions. The residual activity present in the lysosomal fraction from diseased cat liver showed altered pH optimum, two-fold increase in Km with a severely reduced Vmax and increased thermolability compared with the activity in the lysosomal fraction from control liver. The thermal inactivation pattern and Km of the residual activity in the lysosomal fraction is different from the non-lysosomal alpha-mannosidase in the liver of the affected cat. This suggests that the residual activity in the lysosomal fraction of the liver from the affected cat is not due to contamination of non-lysosomal alpha-mannosidase in this fraction. Whether this residual activity represents the properties of the mutant enzyme or yet another minor normal component of lysosomes different from the major inactive mutant or absent lysosomal enzyme remains to be elucidated.

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Mannosidosis: Separation and Characterization of Two Acid α-Mannosidase Forms in Mutant Fibroblasts

Cited by 8 publications

References 14 publications

Mannosidosis: two brothers with different degrees of disease severity

Mannosidosis: two brothers with different degrees of disease severity

Mucopolysaccharidosis type I subtypes. Presence of immunologically cross-reactive material and in vitro enhancement of the residual alpha-L-iduronidase activities.

Characterization of α‐mannosidase in feline mannosidosis

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