title: Characterization of two HEXB gene mutations in Argentinean patients with Sandhoff disease.
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.
authors.affiliation: Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: C A
authors.initials: CA
authors.lastname: Brown
authors.forename: B
authors.initials: B
authors.lastname: McInnes
authors.forename: R D
authors.initials: RD
authors.lastname: de Kremer
authors.forename: D J
authors.initials: DJ
authors.lastname: Mahuran
mesh_terms: D001118:Argentina; D001483:Base Sequence; D002460:Cell Line; D004247:DNA; D004252:DNA Mutational Analysis; D054819:Hexosaminidase B; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D012497:Sandhoff Disease / Q000201:enzymology* / Q000235:genetics*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D004247:DNA; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases