(Circulation. 1995;91:513-520.)
© 1995 American Heart Association, Inc.
Articles |
Unstable Triplet Repeat Diseases
From the Department of Molecular and Human Genetics, Howard Hughes Medical Institute and Human Genome Center, Baylor College of Medicine, Houston, Tex.
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Abstract |
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 Top Abstract IntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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Abstract Seven inherited human disorders are now associated with the intragenic expansion of triplet repeat DNA sequences. These repeats demonstrate extreme instability in both germline and somatic tissue, accounting for the unusual genetic inheritance patterns and symptom variability associated with these diseases.
Key Words: diagnosis • genes • molecular biology • nucleotides • hereditary diseases • polymerase chain reaction
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Introduction |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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In recent years, a new mode of molecular mutation responsible for inherited human disease has come to light. The expansion of trinucleotide repeat DNA sequences within the transcribed regions of genes has been demonstrated to be the underlying genetic defect in seven inherited human disorders: fragile X syndrome,1 2 3 spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease),4 myotonic dystrophy (DM),5 6 7 Huntington's disease (HD),8 spinocerebellar ataxia type 1 (SCA1),9 fragile X E mental retardation (FRAXE),10 and dentatorubral pallidoluysian atrophy (DRPLA).11 12 In all cases, a simple trinucleotide, tandemly repeated DNA sequence exists in the transcribed region of the gene (see Table
). The triplet repeat shows
moderate levels of length variation within the normal population.
However, in patient populations, the repeat has expanded well beyond
the normal range, altering the biological functioning of the gene. In
SBMA, HD, SCA1, and DRPLA, the amplifications are quite small, whereas
for fragile X syndrome, DM, and FRAXE, the amplifications may be very
large, generating alleles containing many thousands of repeats. The
unusual properties of triplet repeat DNA sequences account for the
wide-ranging disease severity and nonmendelian inheritance patterns
associated with these diseases.
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Triplet Repeats in Genes |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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Fragile X Syndrome
Fragile X syndrome is the most common form of mental retardation in males, with an incidence of
1 in 1500 males (see Reference 13).
It also affects, although generally less severely, about 30% of
obligate carrier females. The disease derives its name from the
observation of a fragile site near the tip of the long arm of the X
chromosome, which can be induced in patient's cells when grown under
specific in vitro tissue culture conditions (see Reference 14). The
vast majority of fragile X patients have been shown to carry an
expanded CGG repeat array at the fragile X A site
(FRAXA).1 2 3 The FRAXA repeat lies
within the 5'
untranslated region (UTR) of a gene termed fragile X mental retardation
1 (FMR1).2 Normal individuals have alleles with between 6
and 52 CGG repeats, whereas fully affected fragile X patients have an
allele with greater than 200 repeats.3 Nonpenetrant
fragile X family members carry so-called premutation alleles in the
range of 50 to 200 repeats3 (for a detailed review of the
molecular genetics of fragile X syndrome, see Warren and
Nelson).13
Spinal and Bulbar Muscular Atrophy
SBMA is a sex-limited
dominant disorder associated with
progressive muscle weakness and atrophy in males (see Reference 4). The
underlying molecular defect has been found to be the expansion of a
coding CAG repeat within the first exon of the androgen receptor (AR)
gene.4 The repeat is polymorphic in the normal population,
with 12 to 33 CAG repeats and is approximately doubled in size in
patients with 40 to 62
repeats.4 15 16 17
Myotonic Dystrophy
DM is the most common form of inherited
muscular dystrophy in
adults, with an incidence of 1 in 8000 (see Reference 18). DM
patients carry a CTG expansion in the 3' UTR of a chromosome 19 gene
showing strong homology to serine-threonine protein kinases and termed
myotonin protein kinase (Mt-PK).5 6 7
Normal alleles fall
into the range of 5 to 40 repeats, whereas the vast majority of
individuals carrying a DM chromosome have from 50 to greater than 3000
repeats.5 6 7 Individuals with 50 to
200 repeats are
generally asymptomatic or have relatively mild symptoms, although they
are at increased risk of having affected
children5 6 7 (for
a detailed review of the molecular genetics of DM, see
Wieringa).18
Huntington's Disease
HD was the first disorder to be
genetically linked to a defined
chromosomal region near the telomere of the long arm of chromosome 4,
using DNA markers.19 After an intensive 10-year search,
the HD gene was finally isolated and found to be a novel gene of
unknown function, termed huntingtin.8 The vast majority of
HD patients were found to carry an expansion of a CAG repeat located
within the huntingtin open reading frame, which codes for a
polyglutamine tract.8 Normal alleles have in the range of
9 to 30 repeats and affected HD patients greater than 40 and up to 121
repeats.8 20 21 22
Spinocerebellar Ataxia Type 1
SCA1 is the first of the
inherited ataxias to be defined at the
molecular level. SCA1 has been found to be the result of an expansion
of a coding CAG, also polyglutamine, in a novel gene located on
chromosome 6.9 The repeat is polymorphic in the normal
population, with alleles in the range of 9 to 39 repeats, and expanded
in SCA1 patients, who have from 41 to 81
repeats.9 23 24
Fragile X E Mild Mental Retardation
A small number of
patients with mental retardation and a fragile X
chromosome do not carry the FRAXA expansion. A subset of these patients
has been shown instead to have an expansion at a second fragile site,
FRAXE, 600 kb distal to FRAXA.10 The FRAXE site is also
due to the expansion of a CGG repeat,10 although the
gene(s) affected by this expansion is currently not known. Once again,
this repeat is polymorphic in the normal population (6 to 25 repeats)
and expanded on FRAXE chromosomes (>100
repeats).10 25
FRAXE patients have a similar although generally milder phenotype than
FRAXA patients.10 25
Dentatorubral Pallidoluysian Atrophy
DRPLA is a rare
neurodegenerative autosomal dominant disorder
primarily affecting Japanese individuals. A number of human brain cDNAs
have been shown to contain triplet repeat sequences that are
polymorphic in length in the normal population.26 Using
these genes as candidates for the DRPLA gene, two Japanese groups
simultaneously identified DRPLA patient-specific expansions (49 to 75
repeats)11 12 in the brain cDNA B37, which had
previously
been shown to contain a coding CAG repeat polymorphic in the normal
population (9 to 23 repeats).26
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Genotype-Phenotype Correlations |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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In all of the disorders described above, there is a positive relation between the severity of the symptoms and the size of the expanded array.3 5 6 7 8 9 10 11 12 15 20 21 27 28 29 30 31 32 In fragile X syndrome and FRAXE, once the repeats reach a threshold size (>220 repeats), all males are fully affected and are said to carry a "full mutation" allele. In the other disorders, a more progressive relation is seen. Moreover, the age of onset of symptoms is inversely correlated with the size of the repeat. Thus, patients with larger expansions tend to have an earlier age of onset and increasingly more severe symptoms. This is particularly striking for DM and HD, in which the very largest alleles can result in congenital DM (CDM, see Reference 30) and juvenile-onset HD.8 20 21 22 31 However, these correlations are by no means absolute, and large variations in phenotype still exist between individuals carrying similar-sized expansions. Thus, although the size of the expansion is a major influence on disease severity, the precise prognosis for any one patient is also related to other as yet unknown genetic and/or environmental factors.
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Molecular Diagnosis |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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The cloning of the genes for these diseases has allowed the development of specific DNA-based diagnostic tests to determine the allelic status of individuals in affected pedigrees. For those diseases associated with relatively small expansions, for example, less than 150 repeats, SBMA, HD, SCA1, and DRPLA, allelic status in all individuals may be determined rapidly by polymerase chain reaction (PCR) amplification of the region containing the repeats and sizing by polyacrylamide gel electrophoresis.4 8 9 11 12 For fragile X syndrome, DM, and FRAXE, a similar approach can also be used to identify normal alleles and small expansions.3 5 6 7 10 However, large, expanded alleles are, due to technical limitations of the technique, not amplified using the PCR under standard conditions, producing an apparent null allele in patients. Large expansions in patients may be confirmed using traditional Southern blot length analysis of restriction endonuclease–digested genomic DNA.3 5 6 7 10 Accurate presymptomatic diagnosis is especially important for late onset neurodegenerative disorders in which symptoms may often not develop until after childbearing age.
The availability of highly specific DNA-based tests has allowed the molecular evaluation of prior clinical diagnoses. In the majority of cases, the molecular findings have supported the clinical evaluation. However, a minority of patients do not show the expected expansions in the relevant genes. It is probable that many of these cases represent clinical misdiagnosis of these complex disorders (see Reference 33). Retrospective molecular analysis has already revealed that one family clinically identified as segregating for HD does not carry an expansion in the huntingtin gene but instead has an amplification in the DRPLA gene.34 Furthermore, it is probable that DRPLA is the same disorder as that termed Haw River syndrome in the United States; a simple DNA-based assay will allow this assumption to be tested directly.35 Nevertheless, a proportion of nonexpansion patients probably represents mutations in other genes producing a very similar phenotype (so-called phenocopies, see Reference 33), while others may represent as yet unidentified mutations in the disease gene. Both of these possibilities have now been observed for fragile X syndrome. Two families previously identified as segregating fragile X syndrome actually have expansions not at the FRAXA locus but at FRAXE.25 In addition, one fragile X syndrome patient containing a point mutation in the FMR1 gene and at least three patients with deletions encompassing the FMR1 gene have been identified.36 37 38 39 Although apparent phenocopies have been seen for some of the other disorders, other nonexpansion mutations in the disease gene or mutations in further genes have not yet been reported.
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Hypermutable DNA and Unusual Genetics |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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All of the triplet repeat diseases display the unusual genetic feature of anticipation, that is, the increasing severity and earlier age of onset of the disease in successive generations (see Fig 1
for an example of anticipation in a DM family). Before
the demonstration of the molecular basis of these diseases, the
phenomenon of anticipation was highly debated (see Reference 40).
However, once the molecular basis of the diseases became known, a
potential resolution of this phenomenon became apparent.
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This was first demonstrated for fragile X syndrome, where the particular form of anticipation observed is an increasing penetrance in succeeding generations, known as the Sherman paradox.41 42 One of the most interesting features of fragile X pedigrees is the normal transmitting male (NTM), a normal obligate male carrier of the fragile X chromosome whose daughters are also normal. However, the daughters of NTMs are at high risk of transmitting the disease to their own children.41 The Sherman paradox was resolved when it was shown that the CGG repeat in the FMR1 gene was extremely unstable and frequently enlarged on transmission from mother to child.3 The increasing penetrance of the disease in successive generations correlates with increasing size of the CGG repeat. NTMs were shown to have inherited relatively small alleles in the so-called premutation range.3 These alleles are relatively stable in the male germline with no apparent expansion bias, with the result that the offspring of NTMs are all normal. The premutation alleles, though, do apparently demonstrate significant instability in the female germline such that the grandchildren of NTMs are at high risk of having an expanded disease causing full mutation allele.3 It has since been shown that, despite large expansions in other tissues, sperm from affected fragile X males only contains alleles in the premutation range, consistent with a bias against large expansions in the male germline.43
Similar expansion biases exist in the germline transmission of the
other triplet repeat disease genes to account for the phenomenon of
anticipation. DM displays very strong anticipation as well as parental
sex differences in
transmission5 7 28 40 44 45 46 47 48 49 50
(see Fig 1
). Smaller expanded alleles are unstable in the
germline of both
sexes, and classic adult-onset DM may be inherited from parents of
either sex. CDM, however, occurs in children inheriting very large
alleles and is usually transmitted only by affected mothers. Larger
expansions appear to be relatively stable in the male germline, and
alleles beyond 1000 repeats have not been observed in the sperm of
affected males51 (Monckton et al, unpublished
observations). Allele size, though, does not appear to be the only
determinant in the development of CDM. It has been noted that children
who inherit the DM chromosome from their mother are at greater risk
than if they had inherited a similar-sized allele from their
father.52 This suggests that the affected status of DM
mothers has an adverse in utero effect on their children, or
alternatively, that children inheriting larger alleles from their
father are protected in utero by a normal mother.
The intergenerational instabilities of SBMA, HD, SCA1, and DRPLA show remarkable similarities to each other, although in contrast to fragile X, anticipation is most strongly associated with paternal transmission. The molecular data have indicated that the observed anticipation is associated with an expansion bias on paternal transmission.8 9 11 12 15 16 23 32 53 Relatively few transmissions of the FRAXE expansion have been observed, but it appears that the repeats are unstable in the germlines of both sexes and may apparently expand and contract.10 25
Although germline mutation of expanded alleles generally leads to an increase in allele size, reductions in allele size are occasionally observed. For DM, at least, reductions can occasionally generate alleles that fall into the normal allele size range. However, such DM reversions are rare. Only four events have been observed during pedigree analysis,28 54 55 while direct sperm analysis indicates that considerably less than 1% of gametes from affected males carry revertant alleles (Monckton et al, unpublished observation).
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Somatic Instability |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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The high mutability of some of these expanded alleles is not confined to the germline. FRAXA, FRAXE, and DM display high levels of somatic instability, especially for larger alleles.3 5 6 7 10 In fact, somatic instability may be so high that gel electrophoresis based–size analysis of expanded alleles in somatic tissue usually results not in a discrete band but in a heterogeneous smear of multiple unresolved fragments.3 5 6 7 10
Intergenerational differences have been generally determined by comparison of blood DNA between parent and child, and the differences detected have often been assumed to reflect germline instability. However, the demonstration of considerable somatic instability raises doubts as to the actual timing of observed intergenerational differences. In fact, for fragile X, there is now mounting evidence that a significant proportion of the observed intergenerational differences may arise during early embryogenesis.56 57 Consistent with this theory is the observation that the smear seen in different tissues is usually of a similar size and may even be shared between monozygotic twins.56 Furthermore, FRAXA cell lines established from single lymphoblasts with large expansions are stable in vitro.57 Such limited early embryogenic instability has been observed for two murine minisatellite sequences that are frequently triallelic in adult mice.58 59 60 Interestingly, both of these minisatellites have short repeats, one GGCA and the other GGGCA, which incorporate both the FRAXA and DM repeat sequences. Detailed analysis of one of these minisatellites has shown that instability is almost exclusively limited to the first two cell divisions after fertilization.60 The factors that result in the early embryonic instability of repeated DNA sequences are not known.
DM also displays high levels of somatic instability, although in contrast to FRAXA, there are often considerable intertissue differences as well. In particular, it has been shown that the expansion size observed in muscle is consistently larger than that observed in circulating leukocytes.61 62 Whether this is relevant to the mainly muscle-related phenotype associated with DM is currently unknown. Despite the observation of only minimal levels of variation in fetal and neonatal tissue, it also has been speculated that DM also may be unstable during early embryogenesis.18 51 Nonetheless, recent results have demonstrated that the DM expansion continues to enlarge throughout adult life (Wong et al, unpublished observations). Moreover, there appears to be a significant bias toward increasing allele size related directly to patient age. This phenomenon is likely to have confounded attempts to reconcile the observed clinical anticipation with increasing intergenerational allele length. Approximately 7% of DM transmissions apparently involve a contraction of the DM repeat.48 Paradoxically, however, the vast majority of cases do not result in a later age of onset.48 Recent results have indicated that the observed "contractions" may actually be artifacts of age-limited expansion in the children and that the DM allele is even more biased toward germline expansion than previously thought (Monckton et al, unpublished observations).
Of the other diseases, only HD has been demonstrated to show significant levels of somatic instability, with the greatest levels of variation seen between regions of HD brains.63 The major differences are observed between the cerebellum, which has the smallest alleles, and other regions of the brain.63 Whether the observed somatic differences are relevant to HD pathogenesis is yet to be determined.
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Pathogenesis |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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In FRAXA, expansion of the CGG repeat into the full mutation range beyond 220 repeats leads to methylation of the repeat and the nearby CpG island.64 65 66 Methylation in this region dramatically reduces transcription of the FMR1 gene, and no FMR1 protein product is produced in affected males.67 68 The level of disease expression in females is presumably determined by X-inactivation patterns; those cells in which the normal X chromosome is inactivated presumably do not produce any FMR1 protein. The effect of methylation is clearly seen in a case of monozygotic twin sisters who both carry a fully methylated expanded allele of the same size.69 The normal sister has a normal active X chromosome in most of her cells. In contrast, her mentally retarded twin sister has cells mostly containing inactivated normal X chromosomes, and she consequently displays the fragile X phenotype. Thus, it is evident that the major fragile X phenotype results from an expansion-induced methylation event that prevents expression of the FMR1 gene product. The direct relation between loss of FMR1 function and fragile X has been further confirmed in four other patients, three of whom have deletions encompassing the FMR1 gene and one of whom contains a point mutation in the FMR1 gene.36 37 38 39 The FMR protein is highly expressed in brain and gonadal tissues, consistent with the observed phenotype.70 71 72 73 Although the FMR1 protein has been shown recently to contain a conserved RNA binding domain,74 75 76 the specific function of this domain, the normal function of FMR1, and how precisely a loss of FMR1 leads to mental retardation is still unknown.
FRAXE mental retardation also appears to be the result of an expansion-induced, methylation-mediated loss of expression.10 However, the actual gene(s) affected is not known, and it has not been completely ruled out that the 600 kb proximal FMR1 gene is also affected in FRAXE patients.25
It has been suggested that DM pathogenesis also may be a result of expansion-induced loss of function, and, consistent with this, the level of message RNA derived from the affected chromosome appears to be reduced.77 78 79 80 However, one group has detected an apparent increase in message in a CDM fetus.81 To date, no mutations in the DM gene other than the repeat expansion have been reported, and it remains to be clarified whether DM pathogenesis is really a result of loss of function of one allele of the Mt-PK gene, effects on other nearby genes, or a more complex, as yet undetermined disease pathway. Recent in vitro analyses have confirmed that the Mt-PK protein does indeed have kinase activity and can phosphorylate the ß-subunit of the dihydropyridine receptor, although the in vivo relevance of these observations has yet to be determined (Timchenko et al, unpublished observations).
The AR functions normally as a hormone-activated, DNA-binding transcriptional regulator and is highly expressed in the neurons affected in SBMA (see Reference 82). However, although some SBMA males do show some slight androgen insensitivity, SBMA does not result from an expansion-associated loss of function of the AR. Deletions and other clear loss of function mutations of the AR gene are already known to cause testicular feminization in males and are not associated with specific neuronal losses (see Reference 4). Consistent with this, AR molecules carrying expanded arrays are able to bind hormone, although they have slightly lower transregulatory capabilities.82 The CAG expansion in the AR gene must therefore result in a gain of function, potentially mediated by abnormal transregulation.82 Whatever the precise gain of function is, it must be sex limited, since females carrying expanded arrays are unaffected.
The remaining disorders are all autosomal dominants affecting both sexes, with no mutations reported other than the triplet repeat expansions. Remarkably, of the 10 possible trinucleotide DNA sequences, only 2 have so far been identified as producing pathogenic expansions in human genes. Note that of the 64 possible trinucleotide sequences, most are degenerate at the double-stranded DNA sequence level; for instance, a CGG repeat is equivalent to GCG and GGC repeats on the same strand and CCG, CGC, and GCC repeats on the opposite strand. SBMA, DM, HD, SCA1, and DRPLA are all associated with expansion of a CAG repeat (the "CTG" expansion in DM is a "CAG" expansion on the reverse strand). Moreover, in SBMA, SCA1, HD, and DRPLA, the CAG repeat lies within the coding region and gives rise to a polyglutamine tract in the resultant protein. It seems likely that SBMA, HD, SCA1, and DRPLA all represent gains of function of the protein product related to the expanded polyglutamine tract. All of the disorders result in the death of specific populations of neurons, different for each disease. How expansion of a polyglutamine tract may lead to specific cell death is not known. Speculation includes abnormal transglutamination-mediated83 and "glutamine zipper"–mediated84 formation of intramolecular complexes. However, cellular aggregates are not a recognized feature of these disorders, and the exact pathogenic action of expanded polyglutamine tracts remains elusive.
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Molecular Mechanisms of Expansion |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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There has been considerable speculation as to the molecular mechanisms responsible for the dramatic DNA triplet repeat expansions observed at these loci. Hypotheses have largely centered on replication errors, including replication slippage (see Fig 2
)
induced by the adoption of novel secondary structures by the expanded
repeats or the binding of repeat specific proteins (for example, see
Reference 85). More recently, it has been speculated that expansion may
be a length-dependent product of lagging strand
synthesis.86 It has been suggested that once the array
reaches 80 repeats in length, then one Okazaki fragment could be
entirely contained within the array. Such a fragment composed entirely
of repeats, not anchored by unique sequence DNA, could be free to slip
within the array and produce large loopouts that, dependent on the
repair process, could result in expansions.86 Many have
ruled out recombination-based mechanisms, since exchange of flanking
markers has not been observed to accompany de novo length change
mutations; in fact, FRAXA, DM, and HD all show high levels of linkage
disequilibrium with nearby flanking markers, suggesting that full-scale
chromosomal recombination rarely accompanies
mutation.8 87 88 89 90
Nonetheless, recent analyses at tandemly
repeated human minisatellite loci have demonstrated that germline
length change mutation events are biased toward repeat expansion and
frequently involve interallelic exchange yet rarely involve exchange of
flanking markers in a complex gene conversion mutation
process.91 Thus, recombination-based mechanisms, including
gene conversion and sister chromatid exchange,51 cannot be
ruled out as possible mechanisms for triplet repeat instability.
Indeed, one large germline reversion at the DM locus has been
associated with a complex gene conversion event.54
Analyses of occasional variant AGG repeats within the CGG FRAXA array
recently have revealed another tantalizing correlation with human
minisatellite variability.92 Allelic variation at both
FRAXA and at least three human minisatellites are highly polarized
toward one end of the array, strongly suggesting the involvement of
cis-acting sequence elements in the mutation
process.91 92 The high levels of linkage
disequilibrium
observed for FRAXA, DM, and
HD8 87 88 89 90
have generally been
interpreted as a result of the existence of a pool of larger normal
alleles present only on specific "founder" haplotypes.
Alternatively, the linkage disequilibrium may also reflect the
existence of specific predisposing flanking
elements.91 93
The biological nature of any cis-acting elements remains
speculative, but replication origins would seem to be good potential
candidates.
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Other Fragile Sites |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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In addition to the fragile sites associated with mental retardation on the X chromosome, the human genome contains many other fragile sites that may be induced under a variety of tissue culture conditions (see Reference 14). Recently, the molecular basis for a chromosome 16 folate-sensitive fragile site has been identified as expansion of a CGG triplet, which, like fragile X A and E, results in hypermethylation around expanded alleles.94 It is not known whether nearby genes are affected by this hypermethylation, and no disorder has yet been associated with this expansion. However, the fragile site is very rare, no individuals homozygous for the expansion have been identified, and loss of function of one autosomal allele may not be sufficient to express a phenotype. Thus, of the three fragile sites defined at the molecular level, all are associated with expansion of a CGG repeat. It will be of considerable interest to discover the basis of the other fragile sites and the mechanistic basis of chromosomal fragility on expanded alleles.
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Unstable DNA and Colon Cancer |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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Recently, it has been discovered that hereditary nonpolyposis colon cancer (HNPCC) is associated with tumor-specific unstable DNA (see Reference 95). It has been observed that the simple tandem repeat loci commonly used in molecular linkage analyses are frequently mutated in tumor DNA. Increased mutation rates in such tumors have been associated with mutations in at least two genes involved in the DNA mismatch repair system. However, although some of the triplet repeat loci also show increased instability in HNPCC tumor tissue, the changes observed are relatively small additions and deletions, with no reports of dramatic expansions. There is no reason to suppose, and no evidence to support, the direct involvement of mutant alleles of these repair loci in the dramatic expansion of triplet repeats associated with human inherited disorders.
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Conclusions |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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Until recently, DNA was thought to be a relatively stable molecule with new mutations arising relatively infrequently and being stably inherited upon further transmission. However, the last few years have forced us to reevaluate our ideas on the stability of DNA and the association of de novo mutation and human disease. The discovery of hypermutable triplet repeat loci that show unprecedented levels of instability in both the germline and somatic tissue has revolutionized our understanding of the disorders to which they give rise. In particular, unstable DNA provides a molecular explanation for the high degree of symptom variability and the unusual genetic features of the disorders with which it is associated. The cloning of the disease gene and the identification of expanding repeats, despite a critical beginning, nevertheless represent preliminary steps in a pathway to the understanding of the full disease process. Molecular analysis provides at least an immediate diagnostic tool for today's parents, but much still remains to be determined for effective therapies to be developed for tomorrow's patients.
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Acknowledgments |
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We would like to thank Jim Wyngaarden, Belinda Rossiter, Paul Schofield, Nissim Ben-Arie, and Tetsuo Ashizawa for helpful discussions of the manuscript. Dr Monckton is the Muscular Dystrophy Association Sammy Davis Jr Research Fellow, and Dr Caskey is a Howard Hughes Medical Institute Investigator.
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Footnotes |
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Reprint requests to Dr Monckton, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
Received August 15, 1994; accepted October 18, 1994.
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References |
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TopAbstractIntroductionTriplet Repeats in Genes...Genotype-Phenotype Correlations Molecular Diagnosis Hypermutable DNA and Unusual...Somatic Instability Pathogenesis Molecular Mechanisms of...Other Fragile Sites Unstable DNA and Colon...Conclusions References |
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