Objectives: Identification of functional variants underlying inherited diseases and phenotypes is a major bottleneck in human genetics. Approaches to distinguish causal SNPs from those merely in linkage disequilibrium are sorely needed. Currently, SIFT and PolyPhen assign a score to mutations but an approach that can deliver functional predictions would be better. Gentrepid, a candidate gene prediction tool will be extended to facilitate molecular analysis of significant nonsynonymous SNPs providing a physicochemical bioinformatic approach to distinguish harmless polymorphisms from those likely to be pertinent to the phenotype in question.

Methods: In a pilot study, we analysed disease-causing mutations in Lamin A. In this study, we are particularly interested in mutations in the coiled-coil regions as these constitute 3-5% of the coding region in 10% of proteins in the genome. The Lamin-A protein sequence P02545 was retrieved from Uniprot and analysed with multicoil.

Results: Mutations from HGMD indicate 44% of disease - causing mutations in Lamin-A are located in the predicted coil-coil region. Of these, mutations in the “e” and “g” positions of the heptad repeat constitute around half the deleterious mutations whereas the “b” position is the most fault tolerant. The register "c" had the highest modification rate of coil-coil probability between wild and mutant while register "b" had the lowest alteration rate. The most commonly observed phenotype in the predicted coil-coil region is dilated cardiomyopathy followed by Emery-Dreifuss muscular dystrophy – whereas the reverse is true in the non-coiled coil regions.

Conclusion: The study shows some interesting trends: specifically that different phenotypes arise depending on whether the mutation is located within or outside the predicteded coiled-coil regions. And mutations in sites important for attractive electrostatic interactions between the proteins chains are more deleterious than hydrophobic “knobs into holes” packing interactions. The study will be extended to observe all reported mutations in coiled-coil regions in an attempt to achieve statistical significance.