Deficiency of the Hexosaminidase A Activator Protein in a Case of GM₂ Gangliosidosis; Variant AB

Abstract

Summary: A patient is described whose clinical course and pathologic features, including massive brain storage of GM₂ ganglioside in grey matter, are identical with those of classical Tay-Sachs disease despite normal levels of β-N-acetyl hexosaminidase and normal isozyme distribution. The kinetic properties and thermolability of the patient's hexosaminidase are normal. Crude extracts of a postmortem sample of patient's liver can catalyze the hydrolysis of 5.1 pmoles of labeled GM₂ ganglioside/16 h/mg of protein (control liver = 69.9 pmoles/16 h/mg). Addition of partially purified human liver hexosaminidase A activator protein stimulated the hydrolysis of substrate by the patients liver extract by 27-fold, compared to 3-fold for control livers.

Measurement of “activator” in enriched fractions of patient's and control liver showed a reduced (25-30% of control) amount of stimulation of hexosaminidase A catalyzed hydrolysis of GM₂ ganglioside as well as of Asialo-GM₂ ganglioside. The addition of sphingomyelin to reaction mixtures, which is known to inhibit surfactant stimulation of hexosaminidase A, reduced activation of hexosaminidase A by patient's liver preparation to undetectable levels.

Polyacrylamide gel electrophoresis of enriched preparations of control and patient's liver showed a rapidly migrating protein band in control liver corresponding to the activator protein and the absence of this protein band in the patient's liver.

Speculation: We believe that this patient is a genocopy of classical Tay-Sachs disease as a result of a mutation at a gene locus controlling the expression of the hexosaminidase A activator protein. The in vivo requirement of activator protein for hydrolysis of sphingolipid substrates by lysosomal hydrolases may explain the occurrence of other storage disease entities in which normal levels of enzyme are present in the homozygote when assayed using synthetic hydrophilic substrates.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account

Continue with Google

Continue with ORCiD