Biology Reference
In-Depth Information
mechanism underlies fragile X mental retardation syndrome, a condition associ-
ated with the presence of a fragile site on the X chromosome (FRAXA). The
brain-expressed
FMR1
(Xq27.3) gene responsible contains an unusual (CGG)n
repeat in its 5
untranslated region. This repeat exhibits copy number variation of
between 6 and 54 in normal healthy controls, between 52 and >200 in phenotyp-
ically normal transmitting males (the 'premutation') and between 300 and >1000
in affected males (the 'full mutation') (Verkerk
et al
., 1991; Fu
et al
., 1991). Thus a
continuum exists between a copy number polymorphism present in the general
population, the asymptomatic premutation which involves limited expansion of
(CGG)n copy number, and the full mutation which appears to require copy
number expansion beyond a certain threshold value. Expansion of premutations
to full mutations is thought to be a prezygotic event (Moutou
et al
., 1997) and
occurs only during female meiotic transmission. Alleles with a repeat copy num-
ber of <46 do not exhibit elevated meiotic instability. By contrast, for alleles with
52-113 repeat copies, the premutation expands to the full mutation in 70% of
transmissions whereas the corresponding figure for alleles with >90 repeat copies
is 100%. The probability of repeat expansion thus correlates with the repeat copy
number in the premutation allele, consistent with a mechanism of slipped mis-
pairing during replication. Expansion of a sequence can thus itself lead to further
expansion, a process termed 'dynamic mutation' by Richards
et al
. (1992). In
FRAXA, triplet repeat expansion is thought to exert its pathological effects by
down-regulation of
FMR1
gene expression through hypermethylation of the pro-
moter region upstream of the CGG repeat and repression of translation of the
FMR1
transcript.
The discovery of this novel mutational mechanism has led to the recognition
that the expansion of unstable triplet repeats is also responsible for a number of
other human inherited diseases (
Table 8.2
). These often manifest a wide range of
clinical severity and possess unusual features such as increasing severity and pen-
etrance in successive generations ('anticipation') and a sex bias in the transmis-
sion of the disease which correlates with the degree of meiotic instability and
allelic expansion. As can be seen from
Table 8.2
, the nature and location of the
repeat sequence involved varies between disease states as does the extent of the
expansion necessary to bring about symptoms of disease, and of course the mech-
anism of pathogenesis consequent to repeat expansion. It should however be
noted that repeat expansion is not confined to triplet repeats; minisatellite expan-
sion can also occur as in progressive myoclonus epilepsy and the clinically asymp-
tomatic fragile sites FRA16A and FRA16B (
Table 8.2
).
Triplet repeat expansions have so far been found to be associated mainly with
three types of sequence: CAG (with complement CTG), CGG (with complement
CCG) and GAA (with complement TTC). Sequence specificity implies a role for
DNA secondary structure in the expansion mechanism. Such repeats are known
to form stable hairpin loop structures (Chen
et al
., 1995; Gacy
et al
., 1995; Mitas
et
al
., 1995) which become more stable with increasing repeat number. DNA poly-
merase progression appears to be blocked by CTG and CGG repeats and the resul-
tant idling of the polymerase may serve to catalyze slippage leading to repeat
expansion (Kang
et al
., 1995).
A number of diseases are characterized by CAG repeat expansion within the
