Human mannosidosis — The enzymic defect

Carroll, Mark; Dance, N.; Masson, P; Robinson, Donald S.; Winchester, Bryan

doi:10.1016/0006-291x(72)90450-0

Cited by 128 publications

(48 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinically, the disorder presents with mildly coarse facies, mild hepatosplenomegaly, skeletal changes, and psychomotor retardation. Human a-mannosidase is separable into two distinct isoenzymes in fibroblasts (16) and three distinct isoenzymes in liver (7). In the liver, two isoenzymes, supposedly lysosomal, have acidic optimal activity (pH 4.0-4.5), whereas the third, a nonlysosomal component, is optimally active at pH 6.0 (7).…”

Section: Speculationmentioning

confidence: 99%

“…Human a-mannosidase is separable into two distinct isoenzymes in fibroblasts (16) and three distinct isoenzymes in liver (7). In the liver, two isoenzymes, supposedly lysosomal, have acidic optimal activity (pH 4.0-4.5), whereas the third, a nonlysosomal component, is optimally active at pH 6.0 (7). Patients with mannosidosis demonstrate either a complete deficiency or reduced activity of the acidic isoenzymes.…”

Section: Speculationmentioning

confidence: 99%

See 1 more Smart Citation

A New Variant of Mannosidosis with Increased Residual Enzymatic Activity and Mild Clinical Manifestation

Bach

Kohn

Lasch³

et al. 1978

Pediatr Res

View full text Add to dashboard Cite

SummaryA partial deficiency of a-mannosidase was found in cultured skin fibroblasts, serum, and extracts of leukocytes in two siblings with mild mental retardation, delayed speech, a suggestion of coarse or full facies, and limited mobility of the large joints. All other lysosomal enzymes tested were within the normal range. Their father demonstrated intermediate a-mannosidase activity. The addition of 2 mM Zn++ caused a 40% increase of the amannosidase activity in cell extracts of both patients and control subjects. pH profiles and Cellogel electrophoresis of the patients' cells indicated 20% residual activity of the acidic a-mannosidase isoenzyme (pH optimum at 4.0), whereas the activity of the isozyme with pH optimum of 6.0 was normal. Increasing substrate concentration (1-10 mM) demonstrated a 4to 5-fold increase in the a~~a r e n t K, of the acidic a-mannosidase in the patients' fibrobiasts. This residual activity, however, was apparently not sufficient for the normal catabolism of mannose-containing molecules, since electron microscopic examination of the culture; fibroblasts demonstrated numerous lysosomal storage bodies. SpeculationThis family supports the concept that mannosidosis is not a homogeneous syndrome but manifests clinical as well as biochemical heterogeneity. The partial activity of acidic a-mannosidase observed in the cultured fibroblasts (approximately 20%) was insufficient for normal catabolism and allows accumulation of amannoside-containing substrates leading to the abnormal phenctype. Nevertheless, this deduction is based on in vitro studies using a synthetic substrate. The observation that Znf+ causes a 40% stimulation of acidic a-mannosidase activity in the patients' cells agrees with previous findings and may be of significance in the treatment of such cases.Mannosidosis, a deficiency of the acidic form of a-mannosidase (EC 3.3.1.24) (14, 15), results in the accumulation of mannose-rich glycosylated compounds in the lysosomes of various tissues (1,12,15) and the excretion of similar compounds in the urine (13,17,18). Clinically, the disorder presents with mildly coarse facies, mild hepatosplenomegaly, skeletal changes, and psychomotor retardation. Human a-mannosidase is separable into two distinct isoenzymes in fibroblasts (16) and three distinct isoenzymes in liver (7). In the liver, two isoenzymes, supposedly lysosomal, have acidic optimal activity (pH 4.0-4.5), whereas the third, a nonlysosomal component, is optimally active at pH 6.0 (7). Patients with mannosidosis demonstrate either a complete deficiency or reduced activity of the acidic isoenzymes. Structural changes in the acidic isoenzyme demonstrate a 25-to 50-fold increase in apparent K, values and high susceptibility to heat inactivation 10 (4, 6, 8), whereas neutral a-mannosidase is normal (7, 11). The normal neutral a-mannosidase activity may explain the differing residual enzyme activities in various tissues of these patients. We wish to describe a family whose clinical and biochemical findings suggest a new variant of ...

show abstract

Section: Speculationmentioning

confidence: 99%

Section: Speculationmentioning

confidence: 99%

A New Variant of Mannosidosis with Increased Residual Enzymatic Activity and Mild Clinical Manifestation

Bach

Kohn

Lasch³

et al. 1978

Pediatr Res

View full text Add to dashboard Cite

show abstract

“…a-D-mannosidase was assayed using the fluorigenic substrate 4-methylumbelliferyl cy-D-mannopyranoside (Koch-Light Laboratories Ltd, Colnbrook, Bucks) as in [2] except that the substrate concentration was increased to 5 mM in the reaction mixture. One unit of activity is the amount of activity that transforms 1 pmol substrate/min under these conditions.…”

Section: Cy-d-mannosidase Assaymentioning

confidence: 99%

“…ElsevierlNorth-Holland Biomedical Press [2]. Neutral a-D-mannosidase was removed from the liver extract by chromatography on concanavalin A-Sepharose (Pharmacia (GB) Ltd, London) prior to ion-exchange chromatography [ 131.…”

Section: Preparation Of Acidic A-d-mannosidases a And Bmentioning

confidence: 99%

“…Mannosidosis is a lysosomal storage disease of humans [ 1,2] and Angus cattle, [3,4 ] resulting from a deficiency of lysosomal acidic cu-D-mannosidase (EC 3.2.1.24). It has been suggested on the basis of its altered stability and kinetic properties that a mutant enzyme, resulting from a mutation in a structural gene, accounts for the residual acidic a-D-mannosidase in human [5-71 and bovine [8] mannosidosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence that the mutant enzyme in fibroblasts of a patient with mannosidosis does not crossreact with antiserum raised against normal acidic α‐D‐mannosidase

Burditt¹,

Chotai²,

G³

1978

FEBS Letters

View full text Add to dashboard Cite

Mannosidosis

Kistler¹,

Lott²,

Kolodny³

et al. 1977

Arch Neurol

View full text Add to dashboard Cite

Mannosidosis is a rare inborn error of metabolism characterized by deficiency of the lysosomal enzyme alpha-mannosidase and widespread storage of complex carbohydrate, which is enriched in mannose. Two affected unrelated males, aged 6 and 26 years, are reported. Both had a nonprogressive encephalopathy with moderately severe mental retardation. The older patient showed several unique features, including massive gingival hyperplasia associated with histiocytes containing large amounts of a material with the staining characteristics of glycoprotein. The best determinant of mannose storage proved to be the ratio of mannose to other carbohydrates in urinary polysaccharides. The enzyme deficiency in this disease is most convincingly demonstrated at pH values below 4.0. The ability of zinc to activate the mutant enzyme in vitro offers a possible mode of therapy for this disease. Retarded individuals with a Hurler-like appearance and gum hyperplasia of unknown cause should be screened for alpha-mannosidase deficiency.

show abstract

Human mannosidosis — The enzymic defect

Cited by 128 publications

References 9 publications

A New Variant of Mannosidosis with Increased Residual Enzymatic Activity and Mild Clinical Manifestation

A New Variant of Mannosidosis with Increased Residual Enzymatic Activity and Mild Clinical Manifestation

Evidence that the mutant enzyme in fibroblasts of a patient with mannosidosis does not crossreact with antiserum raised against normal acidic α‐D‐mannosidase

Mannosidosis

Contact Info

Product

Resources

About