A molecular dynamics based investigation reveals the role of rare Ribonuclease 4 variants in amyotrophic lateral sclerosis susceptibility.

Missense mutations in certain genes of the Ribonuclease (RNASE) superfamily cause amyotrophic lateral sclerosis (ALS) through loss of either ribonucleolytic or nuclear translocation or both of these activities. While rare ANG/RNASE5 variants have been previously shown to be ALS causative, it is not yet known if any of the reported rare RNASE4 variants can also trigger ALS. The study aims to understand whether rare variants of RNASE4 can manifest ALS through similar loss-of-function mechanisms. Molecular dynamics (MD) simulations were performed on wild-type and all reported rare RNASE4 variants to study the structural and dynamic changes in the catalytic triad and nuclear localization signal residues responsible for ribonucleolytic and nuclear translocation activities respectively. Our systematic study comprising a total of 2.1 μs MD simulations reveal that three rare variants M29I, H72P and R95W would lose their ribonucleolytic activity as a result of conformational alteration of catalytic residue His116, and the R31T and R32W variants would lose their nuclear translocation ability due to local folding and reduced solvent accessibility of QRR residues. Our results show that five among the 20 known rare variants in RNASE4 (M29I, H72P, R95W, R31T and R32W) are possibly deleterious and may manifest ALS due to loss-of-function mechanisms. Overall, this is the first study to demonstrate that although rare and not yet clinically correlated, certain rare RNASE4 variants could cause ALS due to their loss-of-function characteristics and highlights the need to discover novel RNASE variants for a comprehensive understanding of structure-function-disease relationships and design effective therapeutics.