Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.

Abstract

Initial investigations demonstrated that only 3/34 "Tay-Sachs chromosomes" in 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (7 black and 15 non-Jewish Caucasian) had either of the two mutations commonly found in the Jewish population. To determine the nature and incidence of the alterations in this non-Jewish population we have utilized PCR, single-strand conformation polymorphism analysis and sequencing to detect new mutations in genomic DNA. Fourteen primer sets have been utilized to analyze 80% of the coding region and 23/26 splice sites of the gene coding for the alpha chain of hexosaminidase A. Presumed deleterious mutations were discovered in 17/34 chromosomes believed to be carrying a beta-hexosaminidase A alpha-subunit gene mutation. Ten had abnormalities which have been described previously. In the remaining 24 Tay-Sachs disease alleles, six novel mutations predicted to be deleterious were discovered. These include two small deletions (a single-base frameshift and a three-base deletion removing an amino acid), two different nonsense mutations, an initiation codon mutation (ATG----GTG), and a missense mutation (Arg499Cys) in a highly conserved residue. In addition, three presumed nondeleterious mutations were found.