The mucolipidoses: Identification by abnormal electrophoretic patterns of lysosomal hydrolases

Honey, N. K.; Miller, A. T.; Shows, Thomas B.; Opitz, John M.

doi:10.1002/ajmg.1320090310

Cited by 16 publications

(14 citation statements)

References 41 publications

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“…Although all of the ML II and ML III sibships studied have a deficiency of GIcNAc-P transferase activity, there is considerable genetic and biochemical heterogeneity within these disorders (19)(20)(21)(22)(23)(24)(25). We have demonstrated the existence of three distinct complementation groups within ML III (25) and somewhat less defined heterogeneity within ML II (24) that indicate the involvement of several genes.…”

Section: Discussionmentioning

confidence: 76%

“…The residual activity of ML II and those fusions demonstrating corrections of GlcNAc-P III fibroblasts has an abnormal f3HEX band intermetransferase activity. diate to the normal A and B isozyme positions on cel-lulose acetate gels (20). Complementing fusions resulted in a disappearance of this band and increases in the strength of the normal A and B isoenzymes (Fig.…”

Section: Resultsmentioning

confidence: 86%

“…In addition to the distinct differences in the severity of the ML II and ML III disorders, there are suggestions of clinical heterogeneity within the ML III disorder itself, particularly in the extent of mental retardation (2,19). We have reported variations within both disorders in the residual activity of lysosomal enzymes, in their electrophoretic mobility, and lectin binding affinity that suggest heterogeneity (20,21). Varki et al (22), using an assay with an artificial acceptor molecule, a-methyl mannoside, have described an unusual variant of ML III that has a catalytically active GlcNAc-P transferase.…”

Section: Introductionmentioning

confidence: 79%

“…3), suggesting that the complementations within this group may be due to an intragenic mechanism. One of the ML II fibroblasts involved in several of these fusions (LT) has distinctly different residual activities (Table I) and electrophoretic mobilities of several lysosomal enzymes (20,24). It is possible that this variant belongs in a different complementation group and that complementation was prevented by some unknown mechanism in the several fusions between LT and other ML II or ML IIIA fibroblasts that were scored negative.…”

Section: Discussionmentioning

confidence: 99%

“…Cellulose acetate electrophoresis was performed and the ,BHEX isoenzymes visualized with a fluorigenic enzyme-specific stain as previously described (20).…”

Section: Methodsmentioning

confidence: 99%

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Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis.

Mueller¹,

Honey²,

Little³

et al. 1983

J. Clin. Invest.

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A B S T R A C T The genetic relationships between the multiple variants of mucolipidosis II (1-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy) were investigated with a sensitive genetic complementation analysis procedure. These clinically distinct disorders have defects in the synthesis of a recognition marker necessary for the intracellular transport of acid hydrolases into lysosomes. Both disorders are associated with an inherited deficiency of a uridine diphosphate-N-acetyl-glucosamine: lysosomal enzyme precursor N-acetyl-glucosamine-phosphate transferase activity. We had previously shown that both disorders are genetically heterogeneous. Complementation analysis between mucolipidosis II and III fibroblasts indicated an identity of mucolipidosis II with one of the three mucolipidosis III complementation groups (ML IIIA), suggesting a close genetic relationship between these groups. The presence of several instances of complementation within this group suggested an intragenic complementation mechanism. Genetic complementation in heterokaryons resulted in increases in Nacetyl-glucosamine-phosphate transferase activity, as well as in the correction of lysosomal enzyme transport. This resulted in increases in the intracellular levels of several lysosomal enzymes and in the correction of the abnormal electrophoretic mobility pattern of intracellular ,B-hexosaminidase. The findings demonstrate that a high degree of genetic heterogeneity exists within these disorders. N-acetyl-glucosamine-phosphate transferase is apparently a multicomponent en-

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Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

“…Cellulose acetate electrophoresis was performed and the ,BHEX isoenzymes visualized with a fluorigenic enzyme-specific stain as previously described (20).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis.

Mueller¹,

Honey²,

Little³

et al. 1983

J. Clin. Invest.

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Genetic heterogeneity of I‐cell disease is demonstrated by complementation of lysosomal enzyme processing mutants

Shows¹,

Mueller²,

Honey³

et al. 1982

Am. J. Med. Genet.

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I-cell disease (mucolipidosis II) is a fatal childhood disorder affecting the expression of multiple lysosomal acid hydrolases. The disorder is characterized by clinical and biochemical heterogeneity which may reflect different mutants with a similar phenotype. Genetic complementation studies demonstrating genetic heterogeneity within this disorder are described utilizing cultured fibroblasts from 11 different patients. Fibroblasts from I-cell disease (ICD) and from five different lysosomal storage diseases with single structural gene enzyme deficiencies were fused in different combinations, and fractions enriched for multinucleated heterokaryons were isolated and tested for acid hydrolase activity and electrophoretic mobility. In fusions of ICD fibroblasts and various single lysosomal enzyme-deficient fibroblasts, the activity of the deficient enzyme and of the other ICD hydrolases were restored, demonstrating that ICD is not a lysosomal enzyme structural gene defect and that the ICD defect, and not just the single enzyme deficiency, is corrected. In fusions involving only I-cell fibroblasts, at least two complementation groups were identified by the recovery of activities of all lysosomal enzymes tested in heterokaryons. These results demonstrate the existence of genetic heterogeneity within the disorder and suggest that different mutations can result in the I-cell clinical and biochemical phenotype. The data support an altered post-translational processing of lysosomal enzymes as the cause of ICD and suggest that at least two genes participate in this pathway.

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Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase α/β subunits in Korean patients with mucolipidosis type II or type IIIA

Paik

Song

et al. 2005

Hum. Mutat.

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Mucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.

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The mucolipidoses: Identification by abnormal electrophoretic patterns of lysosomal hydrolases

Cited by 16 publications

References 41 publications

Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis.

Mucolipidosis II and III. The genetic relationships between two disorders of lysosomal enzyme biosynthesis.

Genetic heterogeneity of I‐cell disease is demonstrated by complementation of lysosomal enzyme processing mutants

Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase α/β subunits in Korean patients with mucolipidosis type II or type IIIA

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