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str~d synthesis(Fig. 1)”duringreplication.The DNApolymerasethen
beginsto ‘slip’or ‘stutter’on the repeat”-‘causing
,
continualexpansions.
This may occur either during the meiotic divisions to produce eggs
or sperm,or in the rapidlydividingsomatic cells of the early embryo.
The normal range of trinucleotiderepeats is usually less than 50.
In norma\ individuals,the trinucieotide repeat number in a specific
gene may vary within this normal ranges-’and the numberof repeats
is stably transmittedto future generations.In individualsaffected by,
or carriers of, triplet repeat diseases,the repeat numbersare unstable
and expand beyond this normatrange.
r instance, in fragile X syndrome?-‘,an overlap between the
high end of the range af rqzats in normal individuals(6-52 repeats)
and the fow end of the range of repeats (50-230 repeats) in carriers
ion alletes exists, Affected individualscarq at least 600
of pre
refore, the length of the repeat section alone correlates
repeat
with the re~at-instability in this syndrome, but by itself is probably
not sufficient to cause disease.TWOAGG t~nuc~~otidesinte~pt the
CGG repeats in most ~~~~ alleles in fragile X. Whenone or both of
these AGGs is fast, instabilitycharacte~sticof the pre-mutationgenerally occurs. This is usuaily in the 3’tract reiative to transcription,
resulting in 39 or more uninterruptedCCGs. len there are 33 or
fewer uninterruptedCCC&,the repeats are stably inherited’~.
A model has been proposed to explain the generationz3
FMRI CGG repeat alleles by the loss of AGG triplets.
ACG loss in the 3’region may result from the differenti
for the leading and iagging strands to mutate during
Okazaki fragments are more likely to form slipped structures and
therefore to mutate. Pure CGG repesss averaging 70 copies in pre-
region
leads to the synthesis of polyglutankle
in
the AR protein, and presumablya gain of function
of the protein in maIes25.It is possible that females
are protected from this toxic gain-of-functiondisorder by low but protective androgen levels.
Other tr-inlrcleotiderepeat dismscs
Other polyglutamine diseases lead to neurodegenerativedisorders.Poly(CAG)expansionalso
occurs in SCAI, DRPLAand Huntington’sdisease,
resulting in expandedpolyglutaminetracts of considerable length in the gene products. What functions are altered in the resultantproteins remainto
be determined.
Myotonic dystsophy
In myotonic dystrophy,controversy exists over
the effect of triplet repeats on DMPK, the gene
C-G
More stable
~~
c-4.
I
Less stable
re 1. Model for orientation-d
ng out of the template on t
bypassed by DNA polymsrase.
lagging strand causes repeated r
tures adopted by CTG and CAG single-stranded DNA. Reproduced, with permission, fr
One of two (diploid~ copies of a gene in the genome. An
efore it &comes mutated is called a pm-mutation allele.
h&ionic villus - Fetalcells that can be tested
&Q~Y - Myotonie dystrophy in which the tripletis inhe~ted from a parant father than ariSing
and G and are
caused by a single mutant
If a new protein is
it may have fun~tj~na~consciences again of fu~ct~on’~‘
ormal.
pouchy
NA tran~rib~
from the fragile X gene.
~~~t$ - Shott lengths of DNA f
cont$ibut~s to a dominant phenotype if the continued lack of the
~~~~rn~ h&s D c~rn~~~t~v~ effect on the p ~ssion of the di~e~~~,
ssibility is that another gena! is affected downstream of
~~~~ ~~vi~w~d in Rcf, 30),
dt
n) and (c) its nascent trenwipts (vihit@,resultin from the su
horn RNAprucgssingdefects?
transcriptsfrom the ~~~~
gene has
ir! situ hybridization in ~b~b~~sts and muscle biopsies of patients with myotonic dystrophy and normu individu&‘.
ients, but not in natal individuals,postnine expa~~d~d
CTG repeats was detected
up in the nuclei (Fig. 2). This nuclear con-
quint strategiesfor ‘co~eti~~n~
of genetic disordershave fluted
WI recessive csndirions when them is u loss of function. hcrvention
in the triplet Yepitt diseases. where:there may be a gain of function,
p~scnts a si~ni~cal~tc~llen~e. At p~se~~~,
the therapiesfor triplet repeut diseases,where they exist, are aimed at palliationof symptoms.
P~sp~t§ for the future
Sin- ~~e-~c~~
expansions of triplet repeats have been found only
in hurn~s~and not in other species,there anzno known ~imal modeis
of these conditions.The instabUy of repeats, especially in fragile X
syndrome and myotonic dystrophy, has resulltedin rhe Passof these
i%9ssarr.
E. and
F’o~9li~h~, H.
(1944)
(hcs
mutations causing neurological diseases.
with triplet repeats: a new class of
Bionrcd.
P /to~~a~ohv:
48.
I9 I - I47
1Y
Caskcy,C.T. cvul. ( 1992)Triplet repeat mutations in human disease. S~wrrw
30
256.784-789
Richards.R.I. and Sutherland,
G.R. ( 1992) Dynamic mutations,
mutations causing human disease. Cell 70.700-7
:I
new class c,f
I2
fl
WNTCILST. andNelson,D.L. ( 199.3)Trinucleotitlerepeatcxpunsitrns
in ncm,, I
logicltldisease. Cwr: Ol~k. Nwohiol.
Hoffman.E.l?and Jallh,
Morell,
V.
D.
32
2, 75%7SY
( 1993) An expanding enigma. Crw: /GO/. 3. W~-ISY
( 1993) The puzzle of the triple repeats. Sr~icvrt(’X0, I422- 1323
Baa. G. and Lehrach.H. ( 1994)Trinucleotide
repeat expansions and human
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genetic disease, SioEssc~,vsI6,277-284
Brook,J.D. CI ul. ( 1992)Molecular basis of myotonic dystrophy: expansion of
34
a trinuclcotide
35
(CTC) repeat at the 3’ end of a transcript encoding a protein
kinase family member. Cc// 68,799-W
Mahadevan.
M. et d.
(1992) Myotonic dystrophy mutation: an unstable CTG
repeat in !he 3’ untranslated region of the gene. Scicwe 255. 1253-l 255
36