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 
