| Summary: | It is now more than 20 years since the <i>FRA16D</i> common chromosomal fragile site was characterised and the <i>WWOX</i> gene spanning this site was identified. In this time, much information has been discovered about its contribution to disease; however, the normal biological role of <i>WWOX</i> is not yet clear. Experiments leading to the identification of the <i>WWOX</i> gene are recounted, revealing enigmatic relationships between the fragile site, its gene and the encoded protein. We also highlight research mainly using the genetically tractable model organism Drosophila melanogaster that has shed light on the integral role of <i>WWOX</i> in metabolism. In addition to this role, there are some particularly outstanding questions that remain regarding <i>WWOX</i>, its gene and its chromosomal location. This review, therefore, also aims to highlight two unanswered questions. <b><i>Firstly</i></b>, what is the biological relationship between the <i>WWOX</i> gene and the <i>FRA16D</i> common chromosomal fragile site that is located within one of its very large introns? <b><i>Secondly</i></b>, what is the actual substrate and product of the <i>WWOX</i> enzyme activity? It is likely that understanding the normal role of <i>WWOX</i> and its relationship to chromosomal fragility are necessary in order to understand how the perturbation of these normal roles results in disease.
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