CANAVAN DISEASE - MUTATIONS AMONG JEWISH AND NON-JEWISH PATIENTS

Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyze d for mutations in the ASPA gene. Three point mutations-693C-->A, 854A -->C, and 914C-->A-were identified in the coding sequence. The 633C--> A and 914C-->A base changes, resulting in nonsense tyr231-->ter and mi ssense ala305-->glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-->C transversio n converted glu to ala in codon 285. The glu285-->ala mutant ASPA has 2.5% of the activity expressed by the wild-type enzyme. A fourth mutat ion, 433-2(A-->G) transition, was identified at the splice-acceptor si te in intron 2. The splice-site mutation would lead to skipping of exo n 3, accompanied by a frameshift, and thus would produce aberrant ASPA . Of the 128 unrelated Canavan chromosomes analyzed, 88 were from prob ands of Ashkenazi Jewish descent. The glu285-->ala mutation was predom inant (82.9%) in this population, followed by the tyr231-->ter (14.8%) and 433-2(A-->G) (1.1%) mutations. The three mutations account for 38 .8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305- ->glu mutation was found exclusively in non-Jewish probands of Europea n descent and constituted 60% of the 40 mutant chromosomes. Predominan t occurrence of certain mutations among Ashkenazi Jewish and non-Jewis h patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes.