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 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.
Research Institute, Miami Children's Hospital, FL 33155.
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D000581:Amidohydrolases / Q000235:genetics*; D001483:Base Sequence; D017825:Canavan Disease / Q000208:ethnology* / Q000235:genetics*; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005060:Europe; D005091:Exons; D005787:Gene Frequency; D006801:Humans; D007438:Introns; D007585:Jews / Q000235:genetics*; D008969:Molecular Sequence Data; D017354:Point Mutation; D012326:RNA Splicing
D017931:DNA Primers; D000581:Amidohydrolases; C019751:aspartoacylase