by Shawn Bergeron
Tay-Sachs is an autosomal recessive genetic disorder resulting from mutation
of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, alpha-N-acetylhexosaminidase.
This enzyme is necessary for breaking down certain fatty substances, N-galactosamine
from GM2 gangliosides, in brain and nerve cells. These fatty substances
build up and gradually destroy brain and nerve cells, until the entire central
nervous system stops working. There is no known cure for the disease.
More than thirty mutations have been identified in the HEXA gene. These
mutations consist of base pair insertions, base pair deletions, splice site
mutations, and point mutations. All of these mutations alter the protein
product. For example, a four base pair insertion in exon 11 results in an
altered reading frame for the HEXA gene while a three base pair deletion
eliminates the amino acid phenylalinine from the protein product at position
A G to C point mutation at amino acid 180 changes the codon UAC to UAG causing
termination of the polypeptide. A G to A point mutation at amino acid 170
changes the codon CGA to CAA and CGG to CAG which produces glutamine instead
of arganine. A G to C mutation in the splice site of intron 12 has also
been identified. This mutation creates a recognition site for the restriction
enzyme DdeI resulting in abnormal splicing and the production of aberrant
Another splice site mutation has recently been identified. A G to A mutation
at the last nucleotide of exon 5 changes the codon CTG to CTA. This mutation
does not affect the amino acid produced; in both cases it makes leucine.
However, it results in an inefficient and abnormal processing of the mutant
transcript causing the appearance of two low abundance spliced mRNAs. One
is lacking exon 5 and codes for an inactive protein; the other is similar
to normal beta-hexosaminidase alpha mRNA, except for the presence of the
silent G to A mutation which produces small amounts of beta-hexosaminidase
A (2.5%), (Akli).
The lack of beta-hexosaminidase A results in ganglioside accumulation in
the lysosomes causing swelling in many tissues, most notably neurons. Sandhoff
disease has symptoms similar to those associated with Tay-Sachs. The genetic
basis of Sandhoff disease, like Tay-Sachs, is a mutation in the hexosaminidase
A gene. However, Sandhoff disease has a defective beta-chain of beta-hexosaminidase,
whereas Tay-Sachs has a defective alpha-chain of beta-hexosaminidase.
Tay-Sachs is more prevalent in certain ethnic groups, especially Ashkenazi
Jewish populations. One reason why may be due to heterozygote advantage.
Ashkenazi Jewish TSD carriers may be less susceptible to tuberculosis. However,
it has been estimated that it would take more than 300 generations to reach
this level of frequency and the Ashkenazim have only been a separate group
for 70 generations (Shaw and Smith, 1969). Also, one would expect a higher
frequency of TSD in other ethnic groups living in the same conditions, which
is not the case. Another reason may be due to the fact that parents who
have had a child die from TSD will usually have more children than normal
to ensure descendants. Since fifty percent of their children will be heterozygous
for the TSD gene, its frequency increases among the specific group (Koeslag
and Schach, 1984 and 1985).
In conclusion, Tay-Sachs, like many genetic diseases, is complex. There
are many questions that have been answered, but many remain unanswered.
Continuing research and improved techniques may someday answer them.
Said Akli, Jamel Chelly, Christine Mezard, Shawna Gandy, Axel Kahn, and
Livia Poenaru. The Journal of Biological Chemistry (1992), 7324-7329.
J.H. Koeslag and S.R. Schach. Annals of Human Genetics (1985), 291-302.
Shaw and Smith. American Journal of Human Genetics (1969), 595-601.
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