A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the β-Hexosaminidase α-subunit gene in two unrelated American black G(M2)-gangliosidosis (Tay-Sachs disease) patients

Samples of genomic DNA from three unrelated American black infants having both biochemical and clinical features of classical infantile Tay-Sachs disease were sequenced following PCR amplification. A G → T transversion was observed in the AG acceptor splice site preceding exon 5 of the β-hexosaminidase α-subunit gene in the first black family. This transversion changed the acceptor splice site from the consensus sequence, AG, to AT, thereby interfering with splicing at this intron 4/exon 5 junction. The proband was homozygous for this mutation; his mother and a brother are heterozygous. The same mutation was found in a second, apparently unrelated, black G(M2)-gangliosidosis patient. The second patient was a compound heterozygote, as only one allele carried this mutation. The mother and a brother in this second family are carriers for this mutation, while the father and a noncarrier sister are normal for this region of the gene. The third proband did not have this mutation; nor did the mother of a fourth black proband. Eight other independently ascertained non-black, non-Jewish, G(M2)-gangliosidosis families did not have this mutation. The observation of the same novel mutation in two unrelated black G(M2)-gangliosidosis patients indicates that the American black population has segregating within it at least one G(M2)-gangliosidosis mutation which may be specific to this population and not a result of migration.