M. Schroder et al., MOLECULAR-GENETICS OF GM2-GANGLIOSIDOSIS AB-VARIANT - A NOVEL MUTATION AND EXPRESSION IN BHK CELLS, Human genetics, 92(5), 1993, pp. 437-440
The GM2 activator is a hexosaminidase A-specific glycolipid-binding pr
otein required for the lysosomal degradation of ganglioside GM2. Genet
ic deficiency of GM2 activator leads to a neurological disorder, an at
ypical 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. Usi
ng the polymerase chain reaction amplification and direct-sequencing t
echnique, we found the patient to be homozygous for the mutation, wher
eas the parents were, as expected, heterozygous. BHK cells transfected
with a construct of mutant cDNA gave no GM2 activator protein detecta
ble by the Western blotting technique, whereas those transfected by a
wild-type cDNA construct showed a significant level of human GM2 activ
ator protein. The substitution of proline for the normal Arg169 theref
ore appears to result in premature degradation of the mutant GM2 activ
ator, either during the post-translational processing steps or after r
eaching the lysosome. The basis for the phenotype of GM2 gangliosidosi
s variant AB may therefore be either inactivation of the physiological
activator function by the point mutation or instability of the mutant
protein.