A number sign (#) is used with this entry because like other fragile sites it does not represent a gene or a specific phenotype. As indicated below, the fragile site is associated with the CBL2 gene (165360) and is probably related to a specific deletion clinical syndrome.
Folate-sensitive fragile sites are inherited chromosomal aberrations that appear as poorly condensed regions of metaphase chromosomes and are susceptible to breakage under certain experimental conditions. Until the work of Jones et al. (1995), reviewed later, there had been no direct evidence of chromosomal breakage occurring in vivo in carriers of fragile sites. Two folate-sensitive fragile sites, characterized at the molecular level, had been associated with a clinical phenotype: FRAXA (see 309550) with the fragile X syndrome (300624), the second most common cause of mental retardation after Down syndrome, and FRAXE (309548), which is associated with a rare form of mild mental retardation. The molecular basis of FRAXA is the extensive expansion of a CCG-trinucleotide repeat in the 5-prime untranslated region of the FMR1 gene (309550) and associated methylation of an adjacent CpG island. In most cases, the clinical presentation of fragile X syndrome is caused by a reduction in transcription of FMR1 as a result of this FRAXA-induced methylation. Other folate-sensitive fragile sites have been found to be associated with p(CCG)n repeat expansion and changes in regional methylation status. Database searches identified numerous human genes with p(CCG)n repeats located in their 5-prime untranslated regions, but only one of these, CBL2 (165360), was located in the vicinity of a rare folate-sensitive fragile site, FRA11B. Jones et al. (1995) reported the localization of FRA11B to the CBL2 p(CCG)n repeat and demonstrated an association with the chromosome deletion characteristic of Jacobsen (11q-minus) syndrome (147791). Given the very low frequency of both FRA11B and Jacobsen syndrome, an association between them is very unlikely to be due to chance. Hence, the finding of the association was the first demonstration of a direct link between a fragile site and chromosome breakage in vivo. This example is a demonstration of the impact of genetic background in the development of a chromosomal rearrangement.
Jones, C., Penny, L., Mattina, T., Yu, S., Baker, E., Voullaire, L., Langdon, W. Y., Sutherland, G. R., Richards, R. I., Tunnacliffe, A. Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376: 145-149, 1995. [PubMed: 7603564] [Full Text: https://doi.org/10.1038/376145a0]