We have identified three mutations in the beta-hexoseaminidase A (HEXA) gene in 
a juvenile Tay-Sachs disease (TSD) patient, which exhibited a reduced level of 
HEXA mRNA. Two mutations are novel, c.814G>A (p.Gly272Arg) and c.1305C>T (p.=), 
located in exon 8 and in exon 11, respectively. The third mutation, c.1195A>G 
(p.Asn399Asp) in exon 11, has been previously characterized as a common 
polymorphism in African-Americans. Hex A activity measured in TSD Glial cells, 
transfected with HEXA cDNA constructs bearing these mutations, was unaltered 
from the activity level measured in normal HEXA cDNA. Analysis of RT-PCR 
products revealed three aberrant transcripts in the patient, one where exon 8 
was absent, one where exon 11 was absent and a third lacking both exons 10 and 
11. All three novel transcripts contain frameshifts resulting in premature 
termination codons (PTCs). Transfection of mini-gene constructs carrying the 
c.814G>A and c.1305C>T mutations proved that the two mutations result in exon 
skipping. mRNAs that harbor a PTC are detected and degraded by the 
nonsense-mediated mRNA decay (NMD) pathway to prevent synthesis of abnormal 
proteins. However, although NMD is functional in the patient's fibroblasts, 
aberrant transcripts are still present. We suggest that the level of correctly 
spliced transcripts as well as the efficiency in which NMD degrade the 
PTC-containing transcripts, apparently plays an important role in the phenotype 
severity of the unique patient and thus should be considered as a potential 
target for drug therapy.