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Human Molecular Genetics Advance Access originally published online on June 13, 2007
Human Molecular Genetics 2007 16(R2):R150-R158; doi:10.1093/hmg/ddm136
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fragile sites and human disease

Kim Debacker and R.Frank Kooy*

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

* To whom correspondence should be addressed at: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. Tel: +32 38202630; Fax: +32 38202566; Email: frank.kooy{at}ua.ac.be

Received April 6, 2007; Revised May 3, 2007; Accepted May 17, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
 EPILOGUE
 REFERENCES
 
A relationship between fragile sites, specific genomic regions visible as gaps or breaks on cultivated chromosomes, and human disease has been proposed many years ago. Evidence for a role of the ubiquitously expressed common fragile sites characterized by peculiar genome architecture in cancer has been accumulated over the last years. In contrast, a relationship between the second main group of fragile sites characterized by repeat expansion, the rare fragile sites, and mental retardation has been proposed many years ago, but after the molecular cloning of FRAXA and FRAXE both unequivocally involved in mental retardation, no additional fragile sites linked with mental retardation have been cloned for over a decade. The recent cloning of new fragile sites and the identification of the associated genes allow us to readdress this old paradigm and to speculate on the role these might play in human disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
 EPILOGUE
 REFERENCES
 
Fragile sites are gaps, constrictions or breaks on metaphase chromosomes that arise when cells are exposed to a perturbation of the DNA replication process (Fig. 1) (1,2). Fragile sites may be seen on all human chromosomes and are named according to the chromosome band they are observed in, e.g. fra(X)(q27.3) and in addition receive an official symbol of the HUGO nomenclature committee in order of acceptance. For instance, the fra(X)(q27.3) site was called FRAXA (fragile site, X chromosome, A site), because this was the first fragile site detected on the X chromosome. According to their frequency in the population, fragile sites are classified as either common or rare. Common fragile sites are considered present in all individuals, whereas rare fragile sites are present in a small portion of the population with a maximal frequency of 1/20. As of to date, 30 rare and 89 common fragile sites have been described (2–4). A further subdivision is made based on the type of inducing chemicals. The majority of rare fragile sites are expressed when cells are grown in folic acid-deficient medium, whereas some are induced by bromodeoxyuridine (BrdU) or distamycin A. Most common fragile sites are induced by aphidicolin or 5-azacytidine. Table 1 shows the full listing of all fragile sites taken from the Human Genome Database (GDB) (http://www.gdb.org/).


Figure 1
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  		Figure 1. A karyogram showing a hitherto unnamed fragile site on chromosome band 16q21.

 


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  		Table 1. Overview of the rare and the common fragile sites

 
Fragile sites are evolutionary conserved, and orthologs have been found in primates and in mice suggesting a functional role (5–7). A causative relationship of fragile sites with human disease has been suggested. Common fragile sites coincide with cancer breakpoints (2,8). A relationship between rare fragile sites and mental retardation has been proposed many years ago. Surprisingly, after the cloning of FRAXA, associated with fragile X syndrome and FRAXE, associated with a much rarer form of mental retardation (9,10), no other fragile sites from retarded individuals have been cloned for over a decade. The recent cloning of new fragile sites and the identification of the associated genes allow us to readdress this decennia old paradigm.


   MOLECULAR MECHANISM OF THE FRAGILE SITES
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR MECHANISM OF THE...
COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
 EPILOGUE
 REFERENCES
 
Rare fragile sites: repeat expansion
The majority of the rare fragile sites are folate-sensitive (Table 1). This type of fragile site is expressed when cells are cultured in folate-deficient media or by the addition of inhibitors of the folate metabolism (11). To date, seven folate-sensitive fragile sites have been cloned: FRAXA (9), FRAXE (12), FRAXF (13), FRA16A (14), FRA11B (15), FRA10A (16), FRA12A (17) and FRA11A (K. Debacker et al., 2007) (18) (Table 1). All are caused by an expanded CGG-repeat. In the normal population, expansion of the CGG-trinucleotide is rather limited in size (up to 50 in FRAXA). CGG-repeat expansion (from ~200 repeats in FRAXA) results in fragile site expression (2). The repeat enlargement gives rise to hypermethylation of the CGG-repeat and the surrounding CpG island, followed by the transcriptional silencing of the underlying gene. Intermediate CGG-repeat expansions (50 up to 200 in FRAXA) inherit unstably, but are not methylated and are called premutations.

The non-folate-sensitive fragile sites are Distamycin A-sensitive or BrdU inducible (Table 1) (11). At the moment, one Distamycin A-sensitive fragile site, FRA16B, and one BrdU-sensitive fragile site, FRA10B, have been cloned (19,20). Analogous to the folate-sensitive fragile sites, the fragile site FRA16B is caused by repeat expansion, in this case a 33 bp AT-rich minisatellite that is repeated 7–12 times in control individuals, but >2000 times in patients. Sequencing the FRA10B region revealed a variety of AT-rich repeats between 16 and 52 bp in length. PCR showed this region to be very polymorphic. Individuals with FRA10B expression have at least 75 copies of this repeat. Thus, FRA16B and FRA10B are both caused by expansion of AT-rich minisatellite repeats. As shown in Figure 2, the consensus sequences of the AT-rich minisatellites are highly similar (Align; http://www.ebi.ac.uk/servicestmp/needle). Their consensus sequences share 29 identical bases with the highest homology at the 5' ends of the repeats (21).


Figure 2
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  		Figure 2. Comparison of the FRA10B and FRA16B consensus sequences. Identical bases are indicated with vertical lines and different nucleotides with points.

 
Common fragile sites: peculiar genome architecture
Common fragile sites (n = 89, see Table 1) are present as part of the normal chromosome structure in all individuals (22). The majority of the common fragile sites are induced by aphidicolin, an inhibitor of DNA polymerase. A smaller group of common fragile sites are induced by BrdU or 5-azacytidine, an inhibitor of DNA methylation. So far, 15 aphidicolin inducible common fragile sites have been cloned and characterized: FRA1E (23), FRA2G (24), FRA3B (25,26), FRA4F (27), FRA6E (28), FRA6F (29), FRA7E (30), FRA7G (31), FRA7H (32), FRA7I (33), FRA8C (34), FRA9E (35), FRA13A (36), FRA16D (37) and FRAXB (38) (Table 1). Recently, the first 5-azacytidine-sensitive fragile site has been cloned and characterized: FRA1H (39). Common fragile sites extend over large regions of AT-rich sequence, but in contrast to rare fragile sites show no evidence for repeat expansion (22). Using the computer program TwistFlex that measures the local variation in the twist angle between bases, DNA flexibility analysis for several common fragile sites, e.g. FRA1E (23), FRA2G (24), FRA3B (32), FRA7E (40), FRA7H (32), FRA13A (36), FRA16D (41), FRA18C (42) and FRAXB (38), showed a high flexibility of common fragile sites in comparison with non-fragile regions. These flexible sequences are composed of interrupted runs of AT-dinucleotides that resemble AT-rich minisatellite repeats expanded in the rare fragile sites FRA16B and FRA10B (40). The latter rare fragile sites co-locate with genomic regions that harbor the common fragile sites FRA16C and FRA10E, leading to the hypothesis that similar sequences are responsible for the observed fragility at both common and rare fragile sites (40).

As mentioned in the Introduction section, common fragile sites are considered to be present in all individuals. However, several reports mention that the frequency of common fragile sites varies considerably among individuals (43,44). FRA3B and FRA16D are found in nearly every individual, whereas others are observed only in a minority of individuals. The rationale for this inter-individual variability is not known, but it has been hypothesized that sequence polymorphisms may influence fragile site expression (45).

Inheritance pattern of fragile sites
While common fragile sites are present in all chromosomes, rare fragile sites are either inherited from one of the parents or appear seemingly de novo (11). Younger generations in a pedigree have a higher risk of being affected. This ‘anticipation’ was first observed in the fragile X syndrome, where it was called the Sherman paradox (46,47). The inheritance pattern can be explained on the molecular level by the occasional unstable inheritance of repeat sequences. The repeats are polymorphic and stably inherited in the great majority of the population. In a rare minority of individuals, the repeats exceed a threshold size causing remarkable size instability upon transmission from generation to generation, expansions being much more common than contractions. The instability is dependent on the sex of the transmitting parent with maternal transmissions being much more prone to expansion. This sex-bias might provide a molecular explanation for the cytogenetic observation that the fragile site inheritance is predominantly maternal (48,49).

Replication dynamics of fragile sites
Delayed replication at the fragile sites
CGG-repeats are able to adopt unusual non-B DNA structures, such as hairpins, triplex and tetraplex structures (50,51). These secondary structures stall replication fork progression, perturbing the replication process. Hansen et al. (52) showed that the FRAXA-expressing alleles replicate in the G2/M-phase and the non-fragile alleles replicate late in the S-phase. Like the CGG-repeats, the AT-rich repeats of the fragile sites FRA10B and FRA16B also have the ability to form hairpin structures and influence the replication process. Handt et al. (53) analyzed the timing of replication at the FRA10B and FRA16B locus. The FRA10B-expressing alleles replicate in mid S-phase, but showed a delayed replication in comparison with the non-fragile alleles. The FRA16B locus replicates very late in the S-phase and a shift to an even later replication on the expanded alleles. The results show that the non-folate-sensitive fragile sites also affect the dynamics of replication. The genome architecture of common fragile sites, extending over large regions, also influences replication dynamics (22). FRA3B (54), FRA7H (55) and FRA16D (56) are all characterized by a late and/or delayed replication.

The mechanism of repeat elongation and contraction is still poorly understood. In addition to the secondary structures formed by the CGG-repeats and AT-rich minisatellites, components of the replication process, DNA repair and recombination events are believed important for the repeat instability. Several models have been described to explain the mechanism of this instability, e.g. the replication model, the flap model and the synthesis-dependent strand-annealing model. For an overview see Mirkin (57) and Usdin and Grabczyk (50).

Nucleosome assembly at the rare fragile sites
The CGG tracts influence the assembly of nucleosomes, the basic subunits of chromatin, in vitro and in vivo (58). In vitro nucleosome reconstitution, electron microscopy and competitive assembly gel retardation assays showed strong nucleosome exclusion by expanded CGG-repeats. Using in vitro nucleosome reconstitution methods, Hsu and Wang (59) showed that the expanded AT-rich minisatellites constituting FRA16B strongly exclude nucleosome assembly, but only in the presence of Distamycin A, suggesting a common mechanism for the formation of fragile sites.

Cytogenetic expression of fragile sites
Up to now, only expanded CGG-repeats and AT-rich minisatellites have been associated with cytogenetic expression of rare fragile sites. Massive expansion of a CTG-repeat in the 3' untranslated region (UTR) of the DM gene, for instance, causes myotonic dystrophy but does not show fragility. Friedreich’s ataxia, caused by a GAA-repeat expansion of more than a thousand repeat units, has also never been associated with fragile site expression. Why expansion of only some repeats is cytogenetically visible is not clear, but several hypothesises have been proposed (2). First, secondary structures formed at expanded repeat sequences other than found at CGG-repeats or AT-rich minisatellites could be less stable and therefore do not delay the replication process. Secondly, other repeats might be able to express fragility, but the conditions to induce fragility are not known. Finally, in contrast to expanded CGG-repeats and AT-rich minisatellites, which exclude nucleosome formation, expansion of other types of repeats such as CTG and GAA favors nucleosome assembly and thereby forming strongly condensed chromatin.


   COLOCALIZATION OF FRAGILE SITES WITH EVOLUTIONARY BREAKPOINTS
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
FRAGILE SITES AND DISEASE
 EPILOGUE
 REFERENCES
 
Fragile sites are considered in vitro phenomena. In vivo chromosome breakage of fragile sites is rarely observed with the possible exception of the fragile sites FRA11B and FRA18C (15,42). Remarkably, the location of fragile sites within the genome has been conserved between species. Rare and common fragile sites are significantly more frequently found at chromosomal regions repeatedly involved in rearrangements during evolution of the vertebrate lineage (60–62). These data suggest that fragile sites are prone to in vivo breakage during evolution, and might fulfill an important role in genome reorganization.


   FRAGILE SITES AND DISEASE
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
EPILOGUE
 REFERENCES
 
Some of the fragile sites have specifically been linked to human disease.

Rare fragile sites
FRAXA and the fragile X syndrome
The fragile site FRAXA is expressed in fragile X syndrome, the most common form of inherited mental retardation (63). Fragile X syndrome with an incidence of 1 in 4000–6000 is characterized by several clinical and behavioral abnormalities (64). Clinical features include moderate to severe mental retardation, macro-orchidism and an elongated face with prominent ears (65). Behavioral deficits include hyperactivity and sometimes autism. The FRAXA CGG-repeat is located in the 5' UTR of the fragile X mental retardation 1 (FMR1) gene (9). In normal individuals, the CGG-repeat is polymorphic with allele sizes between 6 and 54 repeat units (64,66,67) often interrupted by AGG-triplets. Allele sizes between 55 and 200 repeats are considered premutations. The amount of AGG-triplets in the CGG-tract plays an important role in the stability of the repeat tract (68). In full mutations of >200 CGG-repeats, the CpG island in the promotor of the FMR1 gene is hypermethylated, causing transcriptional silencing of FMR1 and subsequently preventing the synthesis of the FMR1 gene product (FMRP). The protein FMRP with a high expression in neurons and gonads is a RNA-binding protein. FMRP associates with multiple mRNAs and proteins, forming a large messenger ribonucleoprotein complex that interacts with polyribosomes. In neurons, it is involved in local protein synthesis (69).

As premutations are unmethylated, premutation carriers produce FMR1 mRNA and protein, and do not suffer from fragile X syndrome. However, premutation carriers might suffer from a neurodegenerative disorder called fragile X tremor ataxia syndrome (FXTAS), characterized by intention tremor, ataxia, dementia, parkinsonism and autonomic dysfunction at a latter age (70). FXTAS patients also show intranuclear inclusions in the cerebrum and brainstem. Elevated FMR1 mRNA levels were detected in premutation carriers, but the FMRP levels are generally normal or slightly lower. The molecular mechanism of FXTAS is a toxic, RNA gain-of-function.

FRAXE and mental retardation
The FRAXE site is associated with a mild form of mental retardation without specific phenotypic abnormalities. FRAXE mental retardation is extremely rare, 1 in 100 000 to 1 in 150 000 in the general population. The FRAXE CGG- repeat is located in the 5' UTR of the FMR2 gene (12). In normal individuals, the CGG-repeat is polymorphic with allele sizes ranging from 4 to 39 triplet repeats (71). FRAXE expressing individuals have >200 repeats and their CpG island is hypermethylated, causing transcriptional silencing of the FMR2 gene (72). The FMR2 gene belongs to the AF4/FMR2 gene family (73,74). Three members of this gene family AF4, LAF4 and AF5q31 were found to be fused with the MLL gene in infant acute lymphoblastic leukaemia (75–77). Several studies showed that the FMR2 protein that is highly expressed in brain may act as a potent transcription activator (73,78). A second gene, FMR3, also originates from the FRAXE CpG island and is transcribed from the strand opposite to FMR2 (79). Inhibition of FMR3 expression in FRAXE full mutations suggests a possible role of FMR3 in the FRAXE phenotype, but further research is still required.

FRA11B and the Jacobsen syndrome
In vivo chromosome breakage at or near the FRA11B locus has been implicated in Jacobsen syndrome, a distal 11q syndrome (15). This rare chromosome deletion syndrome with an incidence of 1 in 100 000 is characterized by mental retardation, delayed growth and specific malformations. The CGG-repeat associated with the fragile site FRA11B lies within the 5' UTR of the proto-oncogene CBL2. In at least two patients, a deletion of the long arm of chromosome 11 was observed coincident with FRA11B expression in one of the parents. Considering the rarity of each of the two chromosome abnormalities, the authors concluded a causal relationship between CGG-repeat elongation and in vivo chromosome breakage.

FRA12A and mental retardation
The rare, folate-sensitive fragile site FRA12A is one of the sites that have been found in retarded individuals, but also in apparently healthy controls. A preliminary analysis provided strong evidence for a significant dosage effect: individuals with a higher cytogenetic expression of the fragile site have a higher chance of being affected (Fig. 3). We recently identified the CGG-repeat of the fragile site FRA12A to be located at the 5' end of the DIP2B gene (17). The DIP2B protein contains a DMAP1-binding domain, which suggests a role in the DNA methylation machinery. Patients with mental retardation had the longest repeats, and the DIP2B promotor was always methylated. In individuals with FRA12A expression without mental retardation, the promotor region was either methylated or unmethylated. However, real-time expression analysis of the DIP2B gene showed a significantly higher expression in unaffected FRA12A carriers than in affected patients. The combined data suggest that the DIP2B gene, expressed in brain, may influence the neurocognitive problems associated with FRA12A.


Figure 3
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  		Figure 3. Fragile site expression of 41 FRA12A-expressing individuals. Retarded patients with FRA12A expression are indicated in black and non-retarded FRA12A carriers are indicated in grey.

 
Common fragile sites
FRA3B, FRA16D and cancer
Common fragile sites are involved in sister chromatid exchange, deletions and translocations (80). It has also been demonstrated that common fragile sites are preferred sites for plasmid integration and trigger intra-chromosomal gene amplification events (81,82). Moreover, they are involved in somatic rearrangements found in the chromosomes of cancer cells. These rearrangements include homozygous deletions and translocations, frequently inactivating the associated genes (83). The most prominent example is FRA3B located at the chromosome band 3p14.2. This fragile site maps within the tumor suppressor gene FHIT, frequently deleted in cancers including gastrointestinal tract, cervical, lung and breast cancers (84). The FHIT gene spans >1.5 Mb and contains a familial kidney cancer-associated translocation breakpoint t(3;8)(p14.2;q24) and papilloma virus integration sites (85). The second most frequently observed fragile site FRA16D is located at 16q23.2 and associated with the tumor suppressor WWOX. Like the FHIT gene, WWOX is a large gene spanning a genomic region of ~1.0 Mb. Several reports showed that FRA16D is involved in loss-of-heterozygosity in different types of cancer like breast, prostate, lung cancers and esophageal squamous cell carcinoma (80,86). Homozygous deletions were detected in various adenocarcinomas, and chromosomal translocations were found in multiple myeloma.

FRA18C and Beckwith–Wiedemann syndrome
So far, common fragile sites have never been associated with mental retardation syndromes. Recently, we identified a new aphidicolin-sensitive fragile, FRA18C, in the father of a patient with an 18q22-qter truncation and the Beckwith–Wiedemann syndrome (42,87). The chromosomal breakpoint in the patient disrupts the DOK6 gene, involved in the activation of the receptor tyrosine kinases, and is immediately followed by the repetitive telomere motif, (TTAGGG)n. Interestingly, the breakpoint in the progeny coincides with the fragile site in the father. The FRA18C region is highly enriched in AT-rich flexibility islands, characteristic of common fragile site regions. It was speculated that FRA18C may contribute to in vivo chromosome breakage.


   EPILOGUE
TOP
 ABSTRACT
 INTRODUCTION
 MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
 EPILOGUE
REFERENCES
 
After the description of the first fragile site (88), it became clear that multiple types of fragile sites exist, dependent on the frequency in the population and the induction media (43,89). Most fragile sites were found unsolicited in karyotypes from patients with a mental handicap that were investigated to look for structural abnormalities such as a trisomy 21. The fragile site at Xq27.3 appeared associated with a clinically recognizable form of mental retardation (63), and a relationship between fragile sites and mental retardation in general was proposed. In subsequent studies, the occurrence of fragile sites was compared between institutionalized mentally retarded patients and control individuals. In some studies, more fragile sites were found in the mentally handicapped (48,49,90). Other studies reported an identical frequency in both groups, but with a significantly higher rate of expression in the mentally retarded group (91,92), whereas others again reported no difference between the two study populations (48,92–96). Differences in study outcome can be explained, in part, by different criteria for fragile site recognition and by different cell culture conditions necessary for fragile site expression.

However, for a long time, fragile sites apart from FRAXA and FRAXE were considered of no clinical significance (97). Cloning of fragile sites identified the molecular basis of the different types of fragile sites. If we analyze these subcategories, indeed there seems no indication that distamycin or BrdU inducible fragile sites are involved in human disease. FRA10B and FRA16B are not known to be associated with any gene, and no specific clinical problems have been reported in individuals expressing the fragile site. Moreover, both fragile sites as well as FRA17A have been seen in homozygous forms in apparently healthy individuals (98–100). The situation is strikingly different for rare, folate-sensitive sites. Genes are known to be associated with all but one of the cloned fragile sites (Table 1) and these genes are switched off as a result of methylation associated with repeat expansion. None of the folate-sensitive sites have ever been recorded in a homozygous state and associated genes are often strongly evolutionary conserved, suggesting the potential importance for an organism. However, if larger pedigrees are collected, frequently non-retarded individuals expressing the same site as the patient are found. This is sometimes considered as evidence against involvement of mental retardation of that specific site. However, when looking at fragile X pedigrees, some premutation males cytogenetically express the fragile site, but do not suffer from the fragile X syndrome. Yet, such ‘normal transmitting males’ do not challenge the effect of the mutation.

Only the recent cloning of fragile sites allows us to readdress the issue of a potential relationship between rare, folate-sensitive fragile sites and disease. FRA12A is definitively a strong candidate. The associated gene DIP2B is highly expressed in brain and there is evidence for a significant dosage effect (Fig. 3). Moreover, expression analysis of the DIP2B gene showed a lower expression in FRA12A patients with mental retardation than in unaffected carriers of the fragile site (17). The opposite seems true for FRA11A (K. Debacker et al., 2007) (18). The associated gene C11orf8C showed no detectable brain expression and there is no evidence for a dosage effect. The fragile site FRA10A was cloned and the repeat appeared expanded and methylated in patients, silencing the associated gene FRA10AC1 (16). As the parents were not studied for repeat expansion and methylation, a possible causative effect of the mutation cannot be speculated upon. Yet, FRA10A is a candidate for involvement, as in the population studies, the mentally handicapped expressed the site more often than control individuals (48,49,90,92,94). Of FRAXF, only very few patients were studied and so obscure a potential involvement in mental retardation.

Common fragile sites have been involved in cancer breakpoints, but the recent cloning of FRA18C in the father of a patient with a terminal deletion warrants further research on the role of common fragile sites in chromosome truncation disorders, as has previously been suggested for the rare, folate-sensitive site FRA11B.

For a long time, only full mutations were thought to be causative of clinical manifestations. However, premutation carriers may suffer from a neurodegenerative disorder, called FXTAS, caused by elevated FMR1 mRNA levels (70,101). Strikingly, the clinical involvement is believed as a result of expansion of the CGG-repeat itself, causing an increased transcription of the associated gene (102). Thus, over-expression of the associated gene may be a consequence of repeat elongation, not specific for the FMR1 gene. The toxic effect is thought to result from an excess of RNA. Interestingly, in a FRA12A-expressing carrier over-expression of the FRA12A-associated gene, DIP2B, was observed. If increased expression is a general effect of expanded CGG-repeats, it is an intriguing hypothesis to analyze elderly with FXTAS-like clinical manifestations for the expansion of CGG-repeats associated with fragile sites other than FRAXA.

In summary, it can be stated that the recent cloning of novel fragile sites after a long pause revitalized the interest in these cytogenetically visible dynamic mutations. Involvement of at least some of these sites in mental retardation cannot be excluded and justifies further research in this interesting area. Development of novel, molecular screening methods seems a prerequisite, as most families expressing rare fragile sites were described a long time ago and contemporary routine screening methods do not detect fragile sites.


   ACKNOWLEDGEMENTS
 
Financial support for our study on fragile sites was obtained through grants of the Belgian National Fund for Scientific Research—Flanders (FWO) and the University of Antwerp special research fund.

Conflict of Interest statement. None declared.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MOLECULAR MECHANISM OF THE...
 COLOCALIZATION OF FRAGILE SITES...
 FRAGILE SITES AND DISEASE
 EPILOGUE
 REFERENCES
 

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