In Silico Analyses Reveal the Relationship Between ROCK2 Mutations and Laterality Defects

Abstract Laterality defects is a class of congenital disorders resulting from abnormalities in left-right (L-R) axis patterning. Previous studies indicated that the duplication of Rho-associated coiled-coil containing protein kinase 2(ROCK2) had connection with laterality disorders in human and its knockdown led to significant L-R abnormalities in Xenopus and Zebrafish. In this study, we aimed to investigate the association between the mutations of ROCK2 and L-R development in vertebrate. We analyzed a cohort of 65 patients with laterality defects and validated the ROCK2 mutations by polymerase chain reaction (PCR) and direct sequencing. Multiple in silico tools were used to predict the pathogenicity of mutations. We screened out two novel (ROCK2-Q115H, ROCK2-Y416C) and a third rare (ROCK2-A1013T) ROCK2 mutations. The two novel mutations Q115H and Y416C may alter protein properties and impact protein functions.Conclusions: ROCK2-Q115H and ROCK2-Y416C are predicted to be pathogenic and could in part give rise to influence the biological activities of ROCK2 with the change of physicochemical properties and spatial conformation, suggesting that the mutations of ROCK2 may play a role in the pathogenesis of laterality defects.