A BIZARRE genetic 鈥渟tutter鈥� that underlies conditions including
Huntington鈥檚 disease and fragile X syndrome may be much more widespread than
anyone thought, according to new results from a multinational research
team.
Geneticists led by Massimo Pandolfo of Baylor College of Medicine in
Houston have found that Friedreich鈥檚 ataxia, a progressive paralysis that
affects one in 50 000 Europeans, is caused by a stutter within a gene where
three letters of genetic code are repeated over and over (see 鈥淲hen DNA turns
traitor鈥�, 快猫短视频, 25 March 1995, p 28). The surprise is that
Friedreich鈥檚 ataxia is inherited in a different way from Huntington鈥檚 and the
other known triplet repeat diseases. This opens up the possibility that a wide
range of other diseases could be caused by similar genetic malfunctions.
The newly discovered mutation sits on chromosome 9 in a gene named X25. The
mutation is so unexpected that the researchers scoured the gene for months
before recognising it. 鈥淟ast September we were about to say this was not the
right gene,鈥� Pandolfo admits.
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All the other known triplet repeat mutations share common characteristics
which scientists thought were central to the way they cause disease. First,
the
number of repeats tends to increase from one generation to the next, so the
symptoms worsen and start at an earlier age. The repeats tend to be of the
triplets CAG or CGG, which bend DNA into 鈥渉airpins鈥�, a process that is thought
to be crucial to the progressive lengthening of the repeated region. The
mutations are also either in the parts of a gene that are actually 鈥渞ead鈥� to
produce RNA and ultimately protein, or in nearby sequences that regulate the
gene鈥檚 activity. Last, other triplet repeat diseases are inherited in a
dominant fashion, so that only one copy of the faulty geneis needed to cause
disease.
The triplet repeat in X25 is different. The triplet involved is GAA, which
does not seem to form DNA hairpins. More mysteriously, the repeat sits within
a portion of the gene that neither codes for a protein nor has any known
regulatory function. Finally, the mutation is recessive: children must inherit
two copies to be struck by Friedreich鈥檚 ataxia (Science, vol 271, p 1423).
This last finding is especially important, says Stephen Warren of Emory
University in Atlanta, as many unexplained genetic diseases show a recessive
pattern of inheritance. 鈥淩ecessive disorders are the largest class where we
don鈥檛 understand the molecular basis,鈥� he says.