To summarise a bit of the Sutherland and Richards review ;-)
The Fragile X syndrom repeat shows a threshold effect, but other diseases such
as Myotonic dystrophy caused by expansion of the AGC repeat lacks the threshold
effect - just a small increase can cause disease, and the severity or age of
onset is determined by the size of the repeat, which explains anticipation
(earlier onset in successive generations).
The review suggests that the alteration in size of the repeat occurs during
oogenesis and spermatogenesis as this explains the obeserved patterns without
calling for lots of imprinting to prevent paternal repeats expanding in Fragile
X syndrome etc.
Some interesting points...
In Fragile X syndrome the expanded repeat and nearby CpG island become
methlated
which deactivates the gene and causes the disease, but this isn't related to
normal X inactivation because the chromosome 16 fragile site becomes methylated
but is not in an area normally methylated. (if this is badly explained it's
me!)
In Myotonic dystropy the size of the repeat increases more on transmission by
females than in males, although males do pass on the disease, so the disease
shows maternal anticipation.
In Huntingdons disease, spinocerebellar ataxia and dentatorubral
palliodoluysian
atrophy the male-transmitted repeat increases more so these diseases show
paternal anticipation.
Some suggestions as to why these repeats cause the disease...
1) The AGC repeat codes for reiterated glutamines and these may
be involved in protein aggregation by either a)crosslinking or b)polar
zippers
2) the length of the polyglutamine tract may affect certain
transcription factors
and how the repeats expand...
some diseases may be related to mutations in the mis-match repair genes
which allow mistakes in copying the repeat to be retained
"Simple slip-sliding mechanism" - giving rapid expansion of the repeat
when the repeat length exceeds that of an Okazaki fragment (which allows
replication on the wrong side of the DNA replication fork because the
fragment can become an anchor for polymerization)
Some strange observations...
There are no animal models for these trinucleotide repeat expanions leading to
disease! Naturally occuring repeats in animals eg mice are
apparently much shorter and more stable, no-one has observed the dynamic
mutation that amplifies the repeats in humans. Also transgenic models
don't seem to work - I've just seen a paper where expanded repeats where
put into mice, and no phenotypic results were seen. It is possible though that
these animals just don't live long enough to develop the disease, since many
of these diseases in Humans are late-onset disease.
The review also suggested that dynamic mutation may be a mechanism for adaptive
mutation.
Personally I'd recommend anyone interested reads the review as that explains
all this a lot better than I can in this weather!
Jo
