A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black GM2-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 beta-hexosaminidase alpha-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 GM2-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, GM2-gangliosidosis families did not have this mutation.The observation of the same novel mutation in two unrelated black GM2-gangliosidosis patients indicates that the American black population has segregating within it at least one GM2-gangliosidosis mutation which may be specific to this population and not a result of migration.