Abstract
Recent literature has reported multiple critical regions identified through linkage analyses to be potentially relevant in relationship to the aetiology of FIS. This is supportive of the concept that FIS is a complex genetic disorder resulting from multiple genetic interactions and variants. While these areas harbour multiple genes, the work to date has been crucial to our ability to focus and hopefully eliminate massive areas on the genome that are irrelevant to this disorder. As one reviews these genes, however, one should develop a potential algorithm for prioritization of candidate genes. Additionally, one should delve into potential biological mechanisms in relationship to the creation of a spinal deformity. If you were a gene causing scoliosis, what would you look like and how would you function?
One approach to prioritization of candidate genes may be based on the virtue of their direct potential as a biological basis for the deformity, such as genes that encode for a protein of known function, the function of homologous proteins, and the tissue expression pattern. Within the localised region of chromosome 9, one such gene is COL5A1, a precursor for collagen type V alpha chains, a fibrillar forming collagen ubiquitously distributed within the connective tissues. A second group of genes may be those genes encoding regulatory proteins of the extracellular matrix.
Transmembrane 4 superfamily, member 6 (TM4SF6) localised on the critical region on Xq22 is believed to span the cellular membrane with a role in cellular adhesion within the matrix. A third group of genes may maintain a temporal and/or spatial pattern of expression that may relate to the building of the axial skeleton itself. The Iriquois genes isolated on chromosome 5 play multiple roles in embryonic development including anterior/posterior and dorsal/ventral patterning of the central nervous system. Lastly, genes that do not have an intuitive relationship to scoliosis, but are localised within areas of strong linkage, will need to undergo analysis. Multiple examples exist within the reported critical regions within the literature to date.
Another approach to the review of candidate genes within the regions is to think of known genetic disorders in which, 1) scoliosis is recognised as an element of the phenotype, and, 2) the gene and the biological mechanism of the disorder is well known. Immediate potential examples that come to mind are that of known collagen disorders such as osteogenesis imperfecta. The assumption that scoliosis is solely a result of mechanical load imposed upon abnormal connective tissue may be more elementary than what is truly occurring. Another example may be that of neurofibromatosis (gene – NF1). While this particular gene is localised near one of the identified regions, unfortunately, the biological function of the gene in relationship to phenotypic findings is still unknown.
In conclusion, genetic research related to FIS to date has driven us to unbelievable expectations within a relatively short period of time. Further understanding of this complex disease will best be accomplished with thoughtful experimental, orderly design ultimately to have an impact in the therapeutic treatment of this disorder.
Correspondence should be addressed to Jeremy C T Fairbank at The Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX7 7LD, UK
