Abstract
Tay-Sachs disease is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the α-subunit of the lysosomal enzyme, β-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.
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References
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).
Kaback, M. M. in Lysosomes and Lysosomal Storage Diseases (eds Callahan, J. W. & Lowden, J. A.) 331–342 (Raven, New York, 1981).
Rogers, J. H. Int. Rev. Cytol. 93, 187–231 (1985).
Saiki, R. K. et al. Science 230, 1350–1354 (1985).
Myerowitz, R. & Hogikyan, N. D. Science 232, 1646–1648 (1986).
Korneluk, R. G. et al. J. biol. Chem. 261, 8407–8413 (1986).
Proia, R. L. & Sorovia, E. J. biol. Chem. 262, 5677–5681 (1987).
Treisman, R., Orkin, S. H. & Maniatis, T. Nature 302, 591–596 (1983).
DiLella, A. G., Marvit, J., Lidsky, A. S., Gütler, F. & Woo, S. L. Nature 322, 799–803 (1986).
Rees, D. J., Rizza, C. R. & Brownlee, G. G. Nature 316, 643–645 (1985).
Kaback, M. M., Shapiro, L. J., Hirsch, P. & Roy, C. Prog. clin. Biol. Res. 18, 267–279 (1977).
Chase, G. A. & McKusick, V. A. Amer. J. hum. Genet. 24, 339–340 (1972).
Wagener, D., Cavalli-Sforza, L. L. & Barakat, R. Amer. J. hum. Genet. 30, 262–270 (1978).
Myrianthopoulos, N. C. & Melnick, M. Prog. clin. Biol. Res. 18, 95–106 (1977).
Andermann, E., Scriver, C. R., Wolfe, L. S., Dansky, L. & Andermann, F. Prog. Clin. Biol. Res. 18, 161–188 (1977).
Myerowitz, R. & Hogikyan, D. J. biol. Chem. 262, 15396–15399 (1987).
Lawn, R. M., Fritsch, E. F., Parker, R. C., Blake, G. & Maniatis, T. Cell 15, 1157–1174 (1978).
Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).
Wong, C. et al. Nature 330, 384–386 (1987).
Maniatis, T., Fritsch, E. F. & Sambrook, J. in Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, New York, 1982).
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Arpaia, E., Dumbrille-Ross, A., Maler, T. et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature 333, 85–86 (1988). https://doi.org/10.1038/333085a0
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DOI: https://doi.org/10.1038/333085a0
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