Identification of an altered splice site in Ashkenazi Tay-Sachs disease.
Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (ref. 1). A relatively high frequency of carriers (1/27) of a lethal, infantile form of the disease is found in the Ashkenazi Jewish population, but it is not yet evident whether this has resulted from a founder effect and random genetic drift or from a selective advantage of heterozygotes. We have identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient. This change, the substitution of a C for G in the first nucleotide of intron 12 is expected to result in defective splicing of the messenger RNA. A test for the mutant allele based on amplification of DNA by the 'polymerase chain rection and cleavage of a DdeI restriction site generated by the mutation revealed that this case and two other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for two different mutations. The occurrence of multiple mutant alleles warrants further examination of the selective advantage hypothesis.
Arpaia
E
E
Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Dumbrille-Ross
A
A
Maler
T
T
Neote
K
K
Tropak
M
M
Troxel
C
C
Stirling
J L
JL
Pitts
J S
JS
Bapat
B
B
Lamhonwah
A M
AM
D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D013661:Tay-Sachs Disease / Q000235:genetics*
D012333:RNA, Messenger; D004247:DNA