Nature 333, 85 - 86 (05 May 1988); doi:10.1038/333085a0

Identification of an altered splice site in Ashkenazi Tay-Sachs disease

E. Arpaia^*, A. Dumbrille-Ross^*, T. Maler^*, K. Neote^*, M. Tropak^*, C. Troxel^†, J. L. Stirling^*, J. S. Pitts, B. Bapat^*, A. M. Lamhonwah^*, D. J. Mahuran^*, S. M. Schuster^†, J. T. R. Clarke^§, J. A. Lowden & R. A. Gravel^*¶

^*Research Institute, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
^†Department of Chemistry, University of Nebraska–Lincoln, Lincoln, Nebraska 68588, USA
^‡MRC Human Genetics Disease Research Group, King's College London, Kensington Campus, London W8 7AH, UK
^§Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
HSC Research Development Corporation, 88 Elm Street, Toronto, Ontario M5G 1X8, Canada
^¶To whom correspondence is to be addressed.

Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the -subunit of the lysosomal enzyme, -N-acerylhexosaminidase 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 heterozygotes². 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 RNA³. A test for the mutant allele based on amplification of DNA by the 'polymerase chain rection'⁴ 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.

References

1.	O'Brien, J. S. in The Metabolic Basis of Inherited Disease (eds Stanbury, J. B., Wyngaarden, J. B., Fredrickson, D. S., Goldstein, J. L. & Brown, M. S.) 945−969 (McGraw-Hill, New York, 1983).
2.	Kaback, M. M. in Lysosomes and Lysosomal Storage Diseases (eds Callahan, J. W. & Lowden, J. A.) 331−342 (Raven, New York, 1981).
3.	Rogers, J. H. Int. Rev. Cytol. 93, 187−231 (1985). | PubMed | ISI | ChemPort |
4.	Saiki, R. K. et al. Science 230, 1350−1354 (1985). | PubMed | ISI | ChemPort |
5.	Myerowitz, R. & Hogikyan, N. D. Science 232, 1646−1648 (1986). | PubMed | ChemPort |
6.	Korneluk, R. G. et al. J. biol. Chem. 261, 8407−8413 (1986). | PubMed | ISI | ChemPort |
7.	Proia, R. L. & Sorovia, E. J. biol. Chem. 262, 5677−5681 (1987). | PubMed | ChemPort |
8.	Treisman, R., Orkin, S. H. & Maniatis, T. Nature 302, 591−596 (1983). | Article | PubMed | ISI | ChemPort |
9.	DiLella, A. G., Marvit, J., Lidsky, A. S., Gütler, F. & Woo, S. L. Nature 322, 799−803 (1986). | Article | PubMed | ISI | ChemPort |
10.	Rees, D. J., Rizza, C. R. & Brownlee, G. G. Nature 316, 643−645 (1985). | Article | PubMed | ISI | ChemPort |
11.	Kaback, M. M., Shapiro, L. J., Hirsch, P. & Roy, C. Prog. clin. Biol. Res. 18, 267−279 (1977). | PubMed | ChemPort |
12.	Chase, G. A. & McKusick, V. A. Amer. J. hum. Genet. 24, 339−340 (1972). | PubMed | ChemPort |
13.	Wagener, D., Cavalli-Sforza, L. L. & Barakat, R. Amer. J. hum. Genet. 30, 262−270 (1978). | PubMed | ChemPort |
14.	Myrianthopoulos, N. C. & Melnick, M. Prog. clin. Biol. Res. 18, 95−106 (1977). | PubMed | ChemPort |
15.	Andermann, E., Scriver, C. R., Wolfe, L. S., Dansky, L. & Andermann, F. Prog. Clin. Biol. Res. 18, 161−188 (1977). | PubMed | ChemPort |
16.	Myerowitz, R. & Hogikyan, D. J. biol. Chem. 262, 15396−15399 (1987). | PubMed | ISI | ChemPort |
17.	Lawn, R. M., Fritsch, E. F., Parker, R. C., Blake, G. & Maniatis, T. Cell 15, 1157−1174 (1978). | Article | PubMed | ChemPort |
18.	Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463−5467 (1977). | ChemPort |
19.	Wong, C. et al. Nature 330, 384−386 (1987). | Article | PubMed | ChemPort |
20.	Maniatis, T., Fritsch, E. F. & Sambrook, J. in Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, New York, 1982).