Fragile Sites, Trinucleotide Repeat Expansion, and the Fragile X Syndrome

Abstract

Fragile sites are chromosomal regions that show breaks when cells are exposed to certain drugs or grown in media with a deficiency of folate. The more than 80 common fragile sites can be induced in anyone, while rare fragile sites are seen in only a small proportion of individuals and are inherited in a Mendelian fashion. Fragile sites appear as unstained or stretched regions in the chromosomes (Figs. 20.1 and 22.2). Aphidicolin, an inhibitor of DNA polymerase, induces common fragile sites in a small percentage of cells, while camptothecin, an inhibitor of topoisomerase I, enhances the percentage of cells showing them. Lack of folic acid or thymidine in the culture medium induces folate-sensitive rare fragile sites, such as FRAXA and FRAXE on the X chromosome, while BrdU induces other rare fragile sites, such as FRA10B and FRA16B on chromosomes 10 and 16, respectively. Distamycin A, a peptide that binds in the minor groove of AT-rich DNA, induces some fragile sites, including FRA16B. Mostrare fragile sites, even in the homozygous condition, have no phenotypic effects. The exceptions are FRAXA, the fragile site at Xq27.3, which is responsible for the fragile X mental retardation syndrome, and the nearby FRAXE at Xq28, which is sometimes associated with mild mental retardation.