Fragile Sites and Human Disease

Fragile sites are the cytogenetic manifestation of a peculiar genome structure. Two fundamentally different types occur: rare fragile sites that are characterized by repeat expansion and common fragile sites that consist of AT-rich regions which may stretch over megabases and that are prone to chromosomal rearrangements. In contrast to common fragile sites that are presumably present in all individuals, rare fragile sites are found in maximally 5% of the population. A relationship between the rare fragile site at Xq27.3 and fragile X syndrome, the most common form of inherited mental retardation has been well established. In addition, causative genomic rearrangements within the two most frequently observed common fragile sites in specific tumours were demonstrated. Currently, more than 100 different fragile sites have been described and a potential role for additional fragile sites in human disease, including intellectual disability, autism, neurodegeneration, cancer and chromosome truncation syndromes, is emerging. We use rare fragile sites to clone novel dynamic mutations and investigate their role in disease.

Listing of rare fragile sites

Rare, folate-sensitive fragile sites        
Fragile site Chromosome location associated repeat associated gene other associated transcripts
FRA1M 1p21.3      
FRA2A 2p11.2 (CGG)n AFF3  
FRA2B 2q13      
FRA2K 2q22.3      
FRA5G 5q35      
FRA6A 6p23      
FRA7A 7p11.2 (CGG)n ZNF713  
FRA8A 8q22.3      
FRA9A 9p21      
FRA9B 9q32      
FRA10A 10q23.3 (CGG)n FRA10AC1  
FRA11A 11q13.3 (CGG)n MPPED2/C11orf8C  
FRA11B 11q23.3 (CGG)n CBL  
FRA12A 12q13.1 (CGG)n DIP2B  
FRA12D 12q24.13      
FRA16A 16p13.11 (CGG)n N.D.  
FRA19B 19p13      
FRA20A 20p11.23      
FRA22A 22q13      
FRAXA Xq27.3 (CGG)n FMR1 ASFMR1/FMR4
FRAXE Xq28 (CGG)n AFF2/FMR2 FMR3
FRAXF Xq28 (CGG)n TMEM185A/FAM11A  

 

Rare, distamycin A inducible fragile sites        
Fragile site Chromosome location associated repeat associated gene other associated transcripts
FRA8E 1p21.3      
FRA11I 2p11.2      
FRA16B 2q13 AT-rich minisatellite N.D.  
FRA16E 2q22.3      
FRA17A 5q35      

 

Rare, bromodeoxyuridine inducible fragile sites        
Fragile site Chromosome location associated repeat associated gene other associated transcripts
FRA10B 10q25.2 AT-rich minisatellite N.D.  
FRA12C 12q24      

 

 

FRA16E