CANAVAN DISEASE - GENOMIC ORGANIZATION AND LOCALIZATION OF HUMAN ASPATO 17P13-TER AND CONSERVATION OF THE ASPA GENE DURING EVOLUTION

Canavan disease, or spongy degeneration of the brain, is a severe leuk odystrophy caused by the deficiency of aspartoacylase (ASPA). Recently , a missense mutation was identified in human ASPA coding sequence fro m patients with Canavan disease. The human ASPA gene has been cloned a nd found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon II I) to 514 (exon VI) bases. The exon/ intron splice junction sites foll ow the gt/ag consensus sequence rule. Southern blot analysis of genomi c DNA from human/mouse somatic cell hybrid cell lines localized ASPA t o human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine asp a gene has also been cloned, and its exon/intron organization is ident ical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomi c DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. T he specificity of cross-species hybridization of coding sequences sugg ests that aspartoacylase has been conserved during evolution. It shoul d now be possible to identify mutations in the noncoding genomic seque nces that lead to Canavan disease and to study the regulation of ASPA. (C) 1994 Academic Press, Inc.