Characterization of Two HEXB Gene Mutations in Argentinean Patients With Sandhoff Disease

Biochim Biophys Acta. 1992 Oct 13;1180(1):91-8. doi: 10.1016/0925-4439(92)90031-h.

Abstract

Beta-hexosaminidase A (beta-N-acetyl-D-hexosaminidase, EC 3.2.1.5.2) is a lysosomal hydrolase composed of an alpha- and a beta-subunit. It is responsible for the degradation of GM2 ganglioside. Mutations in the HEXB gene encoded beta-subunit cause a form of GM2 gangliosidosis known as Sandhoff disease. Although this is a rare disease in the general population, several geographically isolated groups have a high carrier frequency. Most notably, a 1 in 16-29 carrier frequency has been reported for an Argentinean population living in an area contained within a 375-km radius from Córdoba. Analysis of the genomic DNA of two patients from this region revealed that one was homozygous for a G to A substitution at the 5' donor splice site of intron 2. This mutation completely abolishes normal mRNA splicing. The other patient was a compared of the intron 2 G-->A substitution and a second allele due to a 4-bp deletion in exon 7. The beta-subunit mRNA of this allele is unstable, presumably as a result of an early stop codon introduced by the deletion. Two novel PCR-based assays were developed to detect these mutations. We suggest that one of these assays could be modified and used as a rapid screening procedure for 5' donor splice site defects in other genes. These results provide a further example of the genetic heterogeneity that can exist even in a small geographically isolated population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argentina
  • Base Sequence
  • Cell Line
  • DNA
  • DNA Mutational Analysis
  • Hexosaminidase B
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Polymerase Chain Reaction
  • RNA Splicing
  • RNA, Messenger / genetics
  • Sandhoff Disease / enzymology*
  • Sandhoff Disease / genetics*
  • beta-N-Acetylhexosaminidases / genetics*

Substances

  • RNA, Messenger
  • DNA
  • Hexosaminidase B
  • beta-N-Acetylhexosaminidases