RAHMAN

Integrity of our genomic material is critical for cell survival and faithful inheritance. The newly identified Rahman syndrome (RS) is a rare genetic disease linked to frameshift mutations in the linker-histone H1.4, a critical structural constituent of chromatin, our genomic material.

All disease-causing mutations are located within a narrow locus encoding the carboxy-terminal domain (CTD) of H1.4 responsible for the compaction of genomic DNA. The preliminary findings indicate that the altered electrochemical composition of RS H1.4 CTD disrupts proper genome packaging in the specific case of the one patient, however to what extend the same mechanism applies to all other known patients is not clear.

Furthermore, RS is known to impair DNA repair, suggesting epigenetic alterations reminiscent of a complex disease physiology. This project aims to tap into EuroHPC resources to expand our atomistic-level high performance simulations to characterise the dynamics of all unique RS H1.4 mutants in comparison to their wild-type (WT) counterparts.

The goal of this full-scale investigation is to map out the “molecular phenotype” landscape of the RS to improve our understanding of this little-known disease and suggest a potential roadmap toward personalized clinical solutions.