Application of a new in silico strategy to evidencing the role of
missense mutations properties in determining Hemophilia A
Hemophilia A (HA) consists of a genetic X-linked blood disorder. It is
caused by a diversity of F8 gene mutations, with missense type being the
most prevalent. Amino acid substitutions may impact physicochemical
properties of the protein, providing an abundant scenario for
investigation. This work evaluates 71 substitutions contributing to
distinct patients’ phenotypes (mild, moderate, and severe), in terms of
physicochemical alterations (PA - electrostatic potential,
hydrophobicity, surface solvent-accessible/excluded areas, disulfide
disruptions, and substitutions indexes), through an in silico strategy.
PA information extracted from models fuels a hierarchical clustering
analysis (HCA - independently and in combination) in an attempt to
connect mutations and patients’ phenotypes. The combined use of PA over
the analysis of single features seems to better reflect the impact of
substitutions in severity degree, apparently in a domain-dependent way.
Besides, a principal component analysis (PCA) identified prominent
properties impacting clustering results for each domain. Electrostatic
potential has a greater contribution to A3 than C1 domain clustering,
probably by A3 involvement in FVIII activation, for example. The
conjugated use of HCA and PCA is a powerful tool to assess if and what
kind of structural features are involved in FVIII protein functionality
impact and HA disease severity.