My personal scientific background is based in genetics and mutation spectra analysis. I’ve always found that genetics is both informative and definitive. If someone carries an inherited mutation in a particular gene the ‘predisposition’ to a specific phenotype will always exist. How this manifests itself is dependent on our knowledge of gene expression and protein function, but ultimately, the cause is there, plain for all to see . Unfortunately, it is our understanding that is often lagging behind.
Regardless, it is crucial that sequence variation is logged to aid future genotype/phenotype correlation studies or to assess the effect of rare missense variants. Such variants are subtle coding sequence alterations that result in an amino acid change. These variants are often thought to have little effect, but protein behaviour can be affected when a non-polar amino acid is substituted for a polar amino acid for example – such an event may effect the entire structure of the protein and subsequently it’s ability to bind other partners.
How can this help BHD researchers? I suspect that identification of mutational hotspots within the folliculin gene will identify the position of conserved functional domains. Ofcourse this is just theory, but a new locus specific database for mutations in folliculin has been published in this months issue of Human Mutation by Lim et al. The database is accessible online at http://www.lovd.nl/flcn and is exactly the kind of thing needed by the BHD community. I urge all researchers to contribute and share genetic data with the aim of enhancing future research.