GM2-ganglioside metabolism in cultured human skin fibroblasts: unambiguous diagnosis of GM2-gangliosidosis

Raghavan, Subharekha; Krusell, Allan; Lyerla, Timothy A.; Bremer, E.; Kolodny, Edwin H.

doi:10.1016/0005-2760(85)90161-4

Cited by 27 publications

(4 citation statements)

References 33 publications

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“…ANALYSIS OF THE METABOLISM OF LABELED GM2. Incorporation of tritium-labeled calf brain GM, [24, 251 was performed [26]. Skin fibroblasts were grown in medium containing radiolabeled GM, ganglioside (1.8 1 Ci/mmol, 2 X 106 dpm) for 48 hours.…”

Section: Biochemical Studiesmentioning

confidence: 99%

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Navon

Khosravi

Melki

et al. 1997

Annals of Neurology

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Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

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Section: Biochemical Studiesmentioning

confidence: 99%

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Navon

Khosravi

Melki

et al. 1997

Annals of Neurology

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“…(c) how important is compartmentation in the regulation of ganglioside metabolism? The experimental approaches that appear more suitable in the study of these problems involve the administration oflabelled gangliosides to cells cultured in vitro or to animals, followed by recognition of the metabolites produced (Ghidoni et al, 1983b;Fishman et al, 1983;Raghavan et al, 1985;Sonderfeld et al, 1985). The advantages ofthe 'in vitro' model (using, for instance, cultured human skin fibroblasts), are the requirement of low amounts of radiolabelled compounds and the possibility of comparing the metabolic pattern provided by normal cell lines with that of mutant lines lacking some of the lysosomal enzymes involved in ganglioside degradation.…”

Section: Introductionmentioning

confidence: 99%

Incorporation and metabolism of exogenous GM1 ganglioside in rat liver

Ghidoni

Trinchera

Venerando

et al. 1986

Biochemical Journal

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The pathways of metabolic processing of exogenously administered GM1 ganglioside in rat liver was investigated at the subcellular level. The GM1 used was 3H-labelled at the level of long-chain base ([Sph(sphingosine)-3H]GM1) or of terminal galactose ([Gal-3H]GM1). The following radioactive compounds, derived from exogenous GM1, were isolated and chemically characterized: gangliosides GM2, GM3, GD1a and GD1b (nomenclature of Svennerholm [(1964) J. Lipid Res. 5, 145-155] and IUPAC-IUB Recommendations [(1977) Lipids 12, 455-468]); lactosylceramide, glucosylceramide and ceramide; sphingomyelin. GM2, GM3, lactosylceramide, glucosylceramide and ceramide, relatively more abundant shortly after GM1 administration, were mainly present in the lysosomal fraction and reflected the occurrence of a degradation process. 3H2O was also produced in relevant amounts, indicating complete degradation of GM1, although no free long-chain bases could be detected. GD1a and GD1b, relatively more abundant later on after administration, were preponderant in the Golgi-apparatus fraction and originated from a biosynthetic process. More GD1a was produced starting from [Sph-3H]GM1 than from [Gal-3H]GM1, and radioactive GD1b was present only after [Sph-3H]GM1 injection. This indicates the use of two biosynthetic routes, one starting from a by-product of GM1 degradation, the other implicating direct sialylation of GM1. Both routes were used to produce GD1a, but only the first one for producing GD1b. Sphingomyelin was the major product of GM1 processing, especially at the longer times after injection, and arose from a by-product of GM1 degradation, most likely ceramide.

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“…Fibroblasts were grown from skin biopsies and harvested according to Raghavan et al [13]. Galactocerebroside was purchased from Supelco, Inc. (Cat.…”

Section: Enzyme Studiesmentioning

confidence: 99%

Late-Onset Krabbe Disease (Globoid Cell Leukodystrophy): Clinical and Biochemical Features of 15 Cases

1991

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The diagnosis of late-onset variants of Krabbe disease (globoid cell leukodystrophy) has been facilitated by the recognition of galactocerebrosidase deficiency as its biochemical hallmark. Fifteen patients, ages 4–73, are presented. Signs included pes cavus, optic disc pallor, progressive spastic tetraparesis, a sensorimotor demyelinating neuropathy and hypodense lesions in the parieto-occipital periventricular white matter. Although intellect was preserved in more than half the cases, significant intrafamilial variability in mental functioning was encountered in 3 families. Bone marrow transplantation was successful in 1 13-year-old girl, but caused the death of 2 teenage twin sisters.

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GM2-ganglioside metabolism in cultured human skin fibroblasts: unambiguous diagnosis of GM2-gangliosidosis

Cited by 27 publications

References 33 publications

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Juvenile‐onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene

Incorporation and metabolism of exogenous GM1 ganglioside in rat liver

Late-Onset Krabbe Disease (Globoid Cell Leukodystrophy): Clinical and Biochemical Features of 15 Cases

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