Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant
- Institut fuer Organische Chemie und Biochemie der Universitaet, Bonn (Germany); and others
Lysosomal degradation of ganglioside GM2 by {beta}-hexosaminidase A (hex A) requires the presence of the GM2 activator protein (GM2AP) as an essential cofactor. A deficiency of the GM2 activator causes the AB variant of GM2 gangliosidosis, a recessively inherited disorder characterized by excessive neuronal accumulation of GM2 and related glycolipids. Two novel mutations in the GM2 activator gene (GM2A) have been identified by the reverse-transcriptase-PCR method - a three-base deletion, AAG{sup 262-264}, resulting in a deletion of Lys{sup 88}, and a single-base deletion, A{sup 410}, that causes a frameshift. The latter results in substitution of 33 amino acids and the loss of another 24 amino acid residues. Both patients are homoallelic for their respective mutations inherited from their parents, who are heteroallelic at the GM2A locus. Although the cultured fibroblasts of both patients produce normal levels of activator mRNA, they lack a lysosomal form of GM2AP. Pulse/chase labeling of cultured fibroblasts of the patients, in presence and absence of brefeldin A, indicates a premature degradation of both-mutant and truncated-GM2APs in the endoplasmic reticulum or Golgi. These results were supported by in vitro translation experiments and expression of the mutated proteins. When the mutated GM2APs were expressed in Escherichia coli, both mature GM2AP forms turned proved to exhibit only residual activities in an in vitro assay. 26 refs., 7 figs.
- OSTI ID:
- 508223
- Journal Information:
- American Journal of Human Genetics, Vol. 59, Issue 5; Other Information: PBD: Nov 1996
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
METABOLIC DISEASES
DIAGNOSIS
GENETICS
PATIENTS
HEREDITARY DISEASES
PROTEINS
GENE REGULATION
GENE MUTATIONS
GENETIC MAPPING
DNA-CLONING
DNA SEQUENCING
GANGLIOSIDES
METABOLISM
RECESSIVE MUTATIONS
POLYMERASE CHAIN REACTION
AMINO ACIDS
ESCHERICHIA COLI
FIBROBLASTS
DNA HYBRIDIZATION