The AB-variant form of
GM2 gangliosidosis is an inherited
lysosomal storage disease. Biochemical data have linked its cause to the lack of a functional
GM2 activator protein (activator). In the present study we identify a mutation in the gene encoding the activator
protein of an AB-variant patient. These data represent direct evidence that the disease in the patient described here is a result of mutations at the Activator gene locus. A T412----C transition was found in the homozygous form in
cDNA and genomic
DNA from the patient. This
nucleotide change would result in the substitution of Cys138 by an Arg residue in the activator
protein. Whereas the patient's fibroblasts produce apparently normal levels of activator
mRNA, they lack a functional activator
protein. Transfection of either a construct containing the normal activator
cDNA, pAct1, or a
cDNA construct containing the T----C transition caused COS-1 cells to transcribe high levels of activator
mRNA. Lysates from cells transfected with pAct1 produced an elevated level of both pro- and mature forms of the activator
protein, with an accompanying 11-fold enhancement in the ability of purified
hexosaminidase A to hydrolyze
GM2 ganglioside. However, lysates from cells transfected with the mutant
cDNA construct contained only low levels of the pro-activator
protein, which failed to enhance
hexosaminidase A activity significantly above the endogenous level of mock transfected COS cells. We conclude that the T412----C transition in the GM2 Activator gene of the patient is responsible for the disease phenotype.