Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene. Three point mutations-693C→A, 854A→C, and 914C→A-were identified in the coding sequence. The 693C→A and 914C→A base changes, resulting in nonsense tyr231→ter and missense ala305→glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A→C transversion 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 mutation, 433 -2(A→G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285→ala mutation was predominant (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 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305→glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes. Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes.
|Original language||English (US)|
|Number of pages||8|
|Journal||American Journal of Human Genetics|
|State||Published - 1994|
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