CLONING OF THE HUMAN ASPARTOACYLASE CDNA AND A COMMON MISSENSE MUTATION IN CANAVAN DISEASE

Canavan disease, an autosomal recessive leukodystrophy, is caused by d eficiency of aspartoacylase and accumulation of N-acetylaspartic acid in brain. We have cloned the human aspartoacylase (ASP) cDNA spanning 1,435 basepairs, and show that the isolated cDNA expresses aspartoacyl ase activity in bacteria. Furthermore, an A to C base change, at nucle otide 854, has been found in 85% of the 34 Canavan alleles tested so f ar. This base change results in a missense Glu285Ala mutation that is predicted to be part of the catalytic domain of aspartoacylase. The da ta suggest that the catalytic centre of aspartoacylase involves a tria d of Ser, His and Glu residues. Our findings have implications for dia gnosis and screening of Canavan disease.