Characterization of two Turkish beta-hexosaminidase mutations causing Tay-Sachs disease

Ozkara H. A., SANDHOFF K.

BRAIN & DEVELOPMENT, vol.25, no.3, pp.191-194, 2003 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 3
  • Publication Date: 2003
  • Doi Number: 10.1016/s0387-7604(02)00213-9
  • Journal Name: BRAIN & DEVELOPMENT
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.191-194
  • Hacettepe University Affiliated: Yes


Two homoallelic mutations have recently been identified in the alpha-subunit of hexosaminidase A (EC causing the infantile form of Tay-Sachs disease in Turkish patients. Both of these mutations, a 12 bp deletion (1096-1107 or 1098-1108 or 1099-1109) in exon 10 and a point mutation (G1362 to A, Gly454 to Asp) in exon 12, are located in the catalytic domain of the hexosaminidase alpha-chain. In order to determine whether these mutations affect the function of the catalytic domain or result in an instable protein, both mutant cDNAs were overexpressed in COS-1 cells. As judged by Western blotting, transfections of wild-type cDNA produced pro-alpha-chain and mature alpha-chain in parallel with a fivefold increase in cellular hexosaminidase activity using the synthetic substrate 4-methylumbelliferyl beta-N-acetylglucosamine 6-sulfate (MUGS). However, both mutants produced only pro-alpha-chains, although no mature form or detectable hexosaminidase activity towards two different synthetic substrates was observed. These data are consistent with the biochemical phenotype of infantile Tay-Sachs disease. We conclude that the overexpressed mutant pro-alpha-chains were misfolded and could not undergo further proteolytic processing to the active form of the enzyme in the lysosome. (C) 2002 Elsevier Science B.V. All rights reserved.