Evidence for a Hybrid Hexosaminidase Isoenzyme in Heterozygotes for Sandhoff Disease

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1979 May 1

PMID 463876

Citations 9

Authors

J A Lowden

Affiliations

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Abstract

Patients with Sandhoff disease have less than 5% of normal levels of serum or tissue hexosaminidase activity. They are thought to have a defect in the structural gene for the beta chain of hexosaminidase (HEX). Heterozygotes for Sandhoff disease have approximately 50% of the total serum HEX activity of normals and more than 75% of the HEX is heat-labile. In normals, only 55%--65% of serum HEX is heat-labile. Serum HEX separates into three forms on DEAE cellulose chromatography: HEX A, a tetramer of 2 alpha and 2 beta chains, and HEX I and B composed solely of beta chains. The DEAE chromatograms from normals and Sandhoff heterozygotes did not differ in the relative distribution of HEX activity between peaks. In normals, the HEX A peak was heat-labile (60 degrees C for 9 min), but HEX I and B were heat-stable. In Sandhoff heterozygotes, however, HEX I and B were only 50%--53% heat-stable. This suggests the heterozygotes synthesized a hybrid enzyme containing both mutant and wild-type beta chains for HEX. The mutant beta chain renders the isoenzyme less stable to heating.

Citing Articles

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Segregation of Tay-Sachs and Sandhoff alleles in a non-Jewish family.

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References

Neufeld E, Sando G, Garvin A, Rome L . The transport of lysosomal enzymes. J Supramol Struct. 1977; 6(1):95-101. DOI: 10.1002/jss.400060108. View

Price R, Thorpe R, Tucker S, Phillips N . Activity of N-acetyl-beta-D-glucosaminidase, alpha-L-fucosidases and alpha-D-mannosidase in the urine of normal individuals and patients with renal disease. Biochem Soc Trans. 1977; 5(1):248-50. DOI: 10.1042/bst0050248. View

Geiger B, Calef E, Arnon R . Biochemical and immunochemical characterization of hexosaminidase P. Biochemistry. 1978; 17(9):1713-7. DOI: 10.1021/bi00602a020. View

Kaback M, Bailin G, Hirsch P, Roy C . Automated thermal fractionation of serum hexosaminidase: effects of alteration in reaction variables and implications for Tay-Sachs disease heterozygote screening. Prog Clin Biol Res. 1977; 18:197-212. View

Briggs M, Capaldi R . Cross-linking studies on a cytochrome c-cytochrome c oxidase complex. Biochem Biophys Res Commun. 1978; 80(3):553-9. DOI: 10.1016/0006-291x(78)91604-2. View

Lane A, Jenkins T . Two variant hexosaminidase beta-chain alleles segregating in a South African family. Clin Chim Acta. 1978; 87(2):219-28. DOI: 10.1016/0009-8981(78)90341-8. View

Lowden J, Ives E, Keene D, Burton A, Skomorowski M, Howard F . Carrier detection in Sandhoff disease. Am J Hum Genet. 1978; 30(1):38-45. PMC: 1685463. View

Geiger B, Arnon R, Sandhoff K . Immunochemical and biochemical investigation of hexosaminidase S. Am J Hum Genet. 1977; 29(5):508-22. PMC: 1685421. View

Harris H, Hopkinson D, Edwards Y . Polymorphism and the subunit structure of enzymes: a contribution to the neutralist-selectionist controversy. Proc Natl Acad Sci U S A. 1977; 74(2):698-701. PMC: 392360. DOI: 10.1073/pnas.74.2.698. View

10.

Field L, Lowden J, Ray A . Immunoglobulin (Gm) allotypes in a sample of Canadian Ashkenazic Jews. Am J Phys Anthropol. 1978; 48(2):159-64. DOI: 10.1002/ajpa.1330480206. View

11.

Armstrong J, Lowden J, SHERWIN A . Brain isoenzyme of creatine kinase. II. Species specificity of enzyme and presence of inactive form in striated muscle of rabbit and man. J Biol Chem. 1977; 252(10):3112-6. View

12.

Nakagawa S, KUMIN S, NITOWSKY H . Human hexosaminidase isozymes: chromatographic separation as an aid to heterozygote identification. Clin Chim Acta. 1977; 75(2):181-91. DOI: 10.1016/0009-8981(77)90189-9. View

13.

Lalley P, Shows T . Expression of human hexosaminidase-A phenotype depends on genes assigned to chromosomes 5 and 15. Cytogenet Cell Genet. 1976; 16(1-5):192-6. DOI: 10.1159/000130588. View

14.

Srivastava S, Beutler E . Hexosaminidase-A and hexosaminidase-B: studies in Tay-Sachs' and Sandhoff's disease. Nature. 1973; 241(5390):463. DOI: 10.1038/241463a0. View

15.

Tallman J, Brady R, Quirk J, Villalba M, GAL A . Isolation and relationship of human hexosaminidases. J Biol Chem. 1974; 249(11):3489-99. View

16.

Srivastava S, Awasthi Y, Yoshida A, Beutler E . Studies on human beta-D-N-acetylhexosaminidases. I. Purification and properties. J Biol Chem. 1974; 249(7):2043-8. View

17.

Vladutiu G, Rattazzi M . Abnormal lysosomal hydrolases excreted by cultured fibroblasts in I-cell disease (mucolipidosis II). Biochem Biophys Res Commun. 1975; 67(3):956-64. DOI: 10.1016/0006-291x(75)90768-8. View

18.

Ikonne J, Rattazzi M, Desnick R . Characterization of Hex S, the major residual beta hexosaminidase activity in type O Gm2 gangliosidosis (Sandhoff-Jatzkewitz disease). Am J Hum Genet. 1975; 27(5):639-50. PMC: 1762835. View

19.

Yabuuchi H, Sumi K, Okada S, Yutaka T . Chromatographic study of serum hexosaminidase in normal and GM 2-gangliosidosis. Clin Chim Acta. 1974; 53(1):85-9. DOI: 10.1016/0009-8981(74)90355-6. View

20.

Lowden J, Zuker S, Wilensky A, Skomorowski M . Screening for carriers of Tay-Sachs disease: A community project. Can Med Assoc J. 1974; 111(3):229-33. PMC: 1947670. View