Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells
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- Schröder, M., Schnabel, D., Hurwitz, R. et al. Hum Genet (1993) 92: 437. doi:10.1007/BF00216446
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The GM2 activator is a hexosaminidase A-specific glycolipid-binding protein required for the lysosomal degradation of ganglioside GM2. Genetic deficiency of GM2 activator leads to a neurological disorder, an atypical form of Tay-Sachs disease (GM2 gangliosidosis variant AB). Here, we describe a G506 to C transversion (Arg169 to Pro) in the mRNA of an infantile patient suffering from GM2-gangliosidosis variant AB. Using the polymerase chain reaction amplification and direct-sequencing technique, we found the patient to be homozygous for the mutation, whereas the parents were, as expected, heterozygous. BHK cells transfected with a construct of mutant cDNA gave no GM2 activator protein detectable by the Western blotting technique, whereas those transfected by a wild-type cDNA construct showed a significant level of human GM2 activator protein. The substitution of proline for the normal Arg169 therefore appears to result in premature degradation of the mutant GM2 activator, either during the post-translational processing steps or after reaching the lysosome. The basis for the phenotype of GM2 gangliosidosis variant AB may therefore be either inactivation of the physiological activator function by the point mutation or instability of the mutant protein.