Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D

Abstract

It is now more than 20 years since the FRA16D common chromosomal fragile site was characterised and the WWOX 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 WWOX is not yet clear. Experiments leading to the identification of the WWOX 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 WWOX in metabolism. In addition to this role, there are some particularly outstanding questions that remain regarding WWOX, its gene and its chromosomal location. This review, therefore, also aims to highlight two unanswered questions. Firstly, what is the biological relationship between the WWOX gene and the FRA16D common chromosomal fragile site that is located within one of its very large introns? Secondly, what is the actual substrate and product of the WWOX enzyme activity? It is likely that understanding the normal role of WWOX and its relationship to chromosomal fragility are necessary in order to understand how the perturbation of these normal roles results in disease.

Keywords: FRA16D; common chromosomal fragile sites; evolutionary conservation; intragenic homozygous deletion; megabase gene; oxido-reductase specificity.

Figure 1

Location and length of introns in the WWOX genes of different species—with respect to major functional domains of the WWOX proteins of human, mouse, fugu and Drosophila.

Figure 2

Homology between WWOX proteins of different species—Human, Chicken, Drosophila, Fugu, Zebrafish, Mouse. In addition to WW domains and SDR canonical sequences, the putative substrate specificity sequences are indicated (green shading). Not shown but noted, the WWOX orthologue in the evolutionarily distant sea sponge (Amphimedon queenslandica) has WW domains and also has substrate binding domain homology. Furthermore, also not shown but noted, the closest SDR family members in the Opisthokonts (Casaspora owczarzaki) and Caenorhabditis elegans (NP_503155.4 and NP_495501.1) do not have WW domains but do have homology in the putative substrate specificity domain. Highly conserved PEST sequence domain (with 14 of 15 amino acids identical) and the cofactor and catalytic sites that are typical of SDR enzymes are indicated (yellow shading).